J Pharmacol Sci 124, 1 – 6 (2014) Journal of Pharmacological Sciences © The Japanese Pharmacological Society Current Perspective Therapeutic Potential of -Receptor Antagonists in

Yasukatsu Izumi1,*, Katsuyuki Miura2, and Hiroshi Iwao1 1Department of Pharmacology, 2Applied Pharmacology and Therapeutics, Osaka City University Medical School, Osaka 545-8585, Japan

Received October 2, 2013; Accepted November 17, 2013

Abstract. Arginine vasopressin (AVP) is a 9-amino acid peptide that is secreted from the posterior pituitary in response to high plasma osmolality and hypotension. AVP has important roles in circulatory and water homoeostasis, which are mediated by receptors and by AVP receptor subtypes: V1a (mainly vascular), V1b (pituitary), and V2 (renal). Vaptans are orally and intravenously active nonpeptide vasopressin-receptor antagonists. Recently, subtype-selective nonpeptide vasopressin-receptor agonists have been developed. A selective V1a-receptor antago- nist, , has shown initial positive results in the treatment of Raynaud’s disease, dysmen- orrhea, and tocolysis. A selective V1b-receptor antagonist, , has beneficial effects in the treatment of psychiatric disorders. Selective V2-receptor antagonists including , , , and induce highly hypotonic diuresis without substantially affecting the excretion of electrolytes. A nonselective V1a/V2-receptor antagonist, , is used in the treatment for euvolaemic or hypervolemic . Recent basic and clinical studies have shown that AVP-receptor antagonists, especially V2-receptor antagonists, may have therapeutic potential for heart failure. This review presents current information about AVP and its antagonists.

Keywords: arginine vasopressin, , heart failure, antagonist

1. Introduction receptor blockers, , b-adrenoceptor blockers, digitalis glycosides, and inotropic agents (4). Unfortu- The prevalence of heart failure has increased in the nately, they are not enough to reduce mortality. Further- past several decades (1), and congestive heart failure has more, therapeutic options in acute decompensated now emerged as a major public health hazard with grave heart failure have not changed significantly over the implications. Rosamond et al. reported that 2.5% of the past several decades despite advances in the management adult American population (approximately 5.3 million of chronic heart failure. Therefore, the discovery of men and women) suffer from congestive heart failure, novel agents is needed for successful treatment of heart and the medical costs of heart failure in the United States failure. are estimated at approximately $60 billion per year (2). Despite advanced medical care for patients with heart 2. Vasopressin in heart failure failure, the average 5-year survival is about 50% (3). Currently, various types of therapeutic agents are used Arginine vasopressin (AVP) is secreted from the for chronic heart failure as standard treatment, including posterior pituitary in response to elevation in plasma angiotensin-converting enzyme inhibitors, angiotensin- osmolality and decreases in arterial pressure. AVP plays a key role in maintaining both volume homeostasis via *Corresponding author. [email protected] osmotic AVP V2 receptor expressed on the basolateral Published online in J-STAGE on January 7, 2014 doi: 10.1254/jphs.13R13CP membranes of the renal collecting duct principal cells and vascular tone via nonosmotic AVP V1a receptor Invited article expressed in vascular smooth muscle cells (5).

1 2 Y Izumi et al

Fig. 1. Effects of individual subtypes of arginine vasopressin receptors.

Three subtypes of AVP receptors have been identified has detrimental effect in patients with heart failure so far, which belong to rhodopsin-like G-protein–coupled because it leads to increased congestion, while hypo­ receptors (6). The role of each AVP receptor subtype in natremia is associated with increased mortality (12). the pathogenesis of heart failure is shown in Fig. 1. The Intravenous infusion of AVP in patients with heart V1a receptor is found on vascular smooth muscle cells, failure increases systemic vascular resistance and pulmo- hepatocytes, and platelets. Binding of AVP to the V1a nary capillary wedge pressure, while it decreases stroke receptor activates Gq/phospholipase C-b, which results volume and cardiac output. These changes were thought in an increase in intracellular calcium levels and activa- to result from AVP-induced vasoconstriction mediated tion of protein kinase C (5, 7), leading to vasoconstric- by the V1a receptor because no association with alterna- tion, platelet aggregation, and growth of the smooth tion in blood pressure or heart rate was observed (13). muscle cells. Furthermore, stimulation of the V1a receptor is associated The V2 receptor is mainly located on the basolateral with the development of cardiac hypertrophy in experi- membrane of the collecting ducts in the renal medulla mental animal models (14). Thus, chronic AVP stimula- (6). Binding of AVP to the V2 receptor activates adenyl- tion could promote cardiac remodeling similarly to other ate cyclase via Gs protein, which leads to an increase in neurohormonal systems. Elevated AVP levels activate intracellular cyclic adenosine monophosphate (cAMP) the V2 receptor, increase the expression of AQP chan- (7). Elevation of intracellular cAMP facilitates transloca- nels, and cause water retention. As a result, preload and tion of aquaporin (AQP) channels from intracellular pulmonary capillary wedge pressure are increased. vesicles to the apical plasma membrane through activa- tion of protein kinase A, leading to an increase in water 3. Vasopressin-receptor antagonists in heart failure permeability (8). The V1b (V3) receptor is found predominantly in the Selective AVP V2-receptor antagonists induce hypo- anterior pituitary, where it mediates adrenocorticotropin tonic diuresis without substantially affecting the excre- release. It is still unknown what role the V1b receptor tion of electrolytes. Tolvaptan and lixivaptan, V2- plays in heart failure. selective antagonists with KiV2:KiV1a binding affinities Previous studies have documented the presence of of 29:1 and 100:1 in human cells, respectively, have been elevated AVP levels in patients with heart failure extensively studied in clinical trials and experimental (9 – 10). In addition, an increase in AVP levels has been animal models of heart failure. A small, randomized, associated with increasing severity of heart failure (9). placebo-controlled, crossover study showed a similar The increase in AVP levels results in impaired excretion urine output in stable patients with heart failure with of free water in patients with heart failure due to an preserved renal function who received single doses of a increase in the number of AQP channels in the collecting (, 80 mg) or tolvaptan (30 mg) duct (8). This results not only in abnormal water (15). There was no difference in the glomerular filtration retention but also in hyponatremia (11). Water retention rate between the two agents, although furosemide Role of Vasopressin in Heart Failure 3

Table 1. Recent clinical trials using AVP antagonists in heart failure AVP Reference Design, Setting, and Participants Effect antagonist No.

V2-selective antagonist Tolvaptan Randomized, double-blind, placebo-controlled, parallel-group, dose-ranging, · Increase in the net fluid loss, decrease in body (Oral) phase 2 trial conducted at 45 centers in the United States and Argentina weight, and improvement in the rate of and enrolling 319 patients with left ventricular ejection fraction of less worsening heart failure. 18 than 40% and hospitalized for heart failure with persistent signs and · No adverse effects such as changes in blood symptoms of systemic congestion despite standard therapy. pressure, heart rate, or electrolytes. Tolvaptan Two identical prospective, randomized, double-blind, placebo-controlled · Improvement in body weight, peripheral (Oral) trials at 359 sites in North America, South America, and Europe were edema, and patient-assessed dyspnea. conducted during the inpatient period of the Efficacy of Vasopressin · No changes in morbidity or mortality. 19 Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST). A total of 4133 patients hospitalized with heart failure and congestion were studied. Tolvaptan A total of 181 patients with advanced heart failure on standard therapy · Increase in urine output and serum sodium (Oral) were randomized to double-blind treatment with tolvaptan at a single oral levels in a dose-dependent manner. dose (15, 30, or 60 mg) or placebo. · No changes in blood pressure, heart rate, 20 systemic and pulmonary vascular resistance, or cardiac index. Tolvaptan Patients with heart failure, systolic dysfunction, and signs of congestion · Reduction in body weight. Well tolerability. (Oral) were removed from baseline diuretic therapy and placed on a low-sodium · No changes in serum electrolytes, other diet. After a 2-day run-in period, 83 patients were randomized to placebo laboratory values, or blood pressure. 21 (n = 21), monotherapy­ with tolvaptan 30 mg (n = 20), monotherapy with furosemide 80 mg (n = 22) or combination therapy with both agents (n = 20) once daily for 7 days. Lixivaptan The effects of lixivaptan in 42 diuretic-requiring patients with mild-to- · Increase in urine output in a dose-dependent (Oral) moderate heart failure in a randomized, double-blind, placebo-controlled, manner. ascending single-dose study were examined. After overnight fluid depri- · Increase in serum sodium level at higher doses. vation, patients received single-blind placebo on day-1 and double-blind 22 study medication (n = 12) or lixivaptan 10, 30, 75, 150, 250, or 400 mg (n = 5 per dose group) on day 1, followed by 4 h of continued fluid restriction and additional 20 h with ad libitum fluid intake. Non-selective antagonist Conivaptan In a double-blind, multicenter trial, 170 patients hospitalized for worsening · Improvement in urine output. Well tolerability. (intravenous) heart failure and given standard therapy were randomly assigned to treat- · No changes in vital signs, electrolyte distur- 23 ment with conivaptan (20-mg loading dose followed by 2 successive 24 h bances, or cardiac rhythm. continuous infusions of 40, 80, or 120 mg/day) or placebo.

increased urinary sodium and potassium excretion and The Efficacy of Vasopressin Antagonism in Heart decreased renal blood flow. Several studies have reported Failure Outcome Study with Tolvaptan (EVEREST) the effects of AVP-receptor antagonists on human and evaluated the short- and long-term effects of tolvaptan animal heart failure (16 – 17). added to standard therapy within 48 h of hospital admission for heart failure (19). A 60-day treatment with 3.1. Clinical trials (Table 1) tolvaptan, in addition to standard therapy with diuretics, The Acute and Chronic Therapeutic Impact of a improved numerous signs and symptoms of heart Vasopressin Antagonist in Congestive Heart Failure failure without any serious side effects. An improvement (ACTIV in CHF) trial evaluated the short- and inter­ in body weight, peripheral edema, and patient-assessed mediate-term effects of tolvaptan in hospitalized patients dyspnea was observed on days 1 and 7 of tolvaptan with heart failure (18). In addition to the standard therapy, treatment, but the primary outcome variable, mortality, tolvaptan was administered to patients with the signs was not affected. and symptoms of congestive heart failure and left The Effect of Tolvaptan on Hemodynamic Parameters ventricular ejection fraction of less than 40%. Compared in Subjects with Heart Failure (ECLIPSE) trial investi- with the standard-therapy group, the treatment group gated the effect of tolvaptan on hemodynamic parameters showed an increase in the net fluid loss resulting in in patients with heart failure (20), including symptomatic decreased body weight. Although tolvaptan had no heart failure and decreased ejection fraction. Tolvaptan adverse effects such as changes in blood pressure, heart increased urine output and serum sodium levels in a rate, or electrolytes, it did not improve the rate of wors- dose-dependent manner. However, no significant differ- ening heart failure. ences were reported for the secondary endpoints of blood 4 Y Izumi et al pressure, heart rate, systemic and pulmonary vascular could improve cardiac function and mortality. Moreover, resistance, or cardiac index. as most of the patients received concomitant medica- Patients with heart failure, systolic dysfunction and tions, it is difficult to elucidate whether tolvaptan can signs of congestion (e.g., edema, rales), were removed independently improve the ejection fraction in patients from baseline diuretic therapy and placed on a low- with chronic heart failure. sodium diet. And then, they were randomized to placebo, Recently, several studies have been published on monotherapy with tolvaptan, monotherapy with furose- the effects of tolvaptan in rat models of heart failure. mide, or both tolvaptan and furosemide once daily for The diuretic effects of tolvaptan were compared with 7 days (21). Tolvaptan monotherapy without concomi- those of furosemide in rats with chronic heart failure tant loop diuretic therapy reduced body weight when after autoimmune myocarditis (26). Tolvaptan increased compared to placebo without adverse changes in serum the plasma sodium concentration in a dose-dependent electrolytes, during a sodium restricted diet while on manner, while furosemide tended to decrease it. Impor- background medications including angiotensin-converting tantly, plasma renin activity and aldosterone concentra- enzyme inhibitors and b-blockers. tion were significantly increased by furosemide, while A small study of stable patients with mild-to-moderate they were not affected by tolvaptan, suggesting that the heart failure that examined the renal effects of lixivaptan latter has a potential benefit for the treatment of chronic showed that it increased urinary output in a dose- heart failure with edematous conditions by removing dependent manner. The increase in urine volumes was excess water from the body without activating the accompanied by significant increases in solute-free water renin-angiotensin-aldosterone system or causing serum excretion, and serum sodium level was significantly electrolyte imbalance. In hypertensive rats with heart increased at higher doses (22). These observations sug- failure, chronic tolvaptan treatment had beneficial gest that the lixivaptan may be a promising therapeutic effects by preventing the progression of left ventricular agent for the treatment of heart failure. dysfunction and renal injury (27). Furthermore, in rats Trials on conivaptan showed that it significantly with left ventricular dysfunction after myocardial infarc- increased urine output and decreased body weight. tion (MI), long-term tolvaptan therapy improved left Conivaptan, a nonselective V1a/V2-receptor antagonist, ventricular ejection fraction and reduced MI-induced is a combined V1a- and V2-receptor antagonist with macrophage infiltration and interstitial fibrosis in the V2:V1a binding affinity of 10:1. However, it failed to left ventricle. At the same time, tolvaptan was shown improve the clinical status of patients (23). to attenuate MI-induced mRNA expression of atrial and brain natriuretic peptides, which are reliable markers 3.2. Experimental animal models of heart failure (28), as well as monocyte chemotactic The beneficial effects of AVP-receptor antagonists protein-1, transforming growth factor-b1, and endo­ in the treatment of heart failure have been demonstrated thelin-1 in the marginal infarct region (29). Furthermore, in experimental animal models. In dogs with heart failure a 2-week treatment with tolvaptan improved the left induced by rapid right ventricular pacing, oral admin­ ventricular ejection fraction and suppressed MI-induced istration of OPC-21268, a selective V1-receptor antago- left ventricular interstitial fibrosis and mineralocorticoid nist, significantly improved cardiac output and renal receptor expression in rats with acute heart failure after function (24). On the other hand, mozavaptan, a selective MI (30). These observations suggest that tolvaptan may V2-receptor antagonist, increased urinary output, serum have beneficial effects both on acute and chronic heart sodium levels, as well as plasma renin and vasopressin failure, which is partially mediated by the suppression levels, although it did not improve hemodynamic para­ of neurohumoral activation, the renin–angiotensin– meters. In a similar dog model, tolvaptan induced aldosterone system, and inflammation. aquaresis with an increase in free water clearance, result- ing in a significant increase in serum sodium concentra- 4. Conclusions tions and a decrease in cumulative water balance. Furthermore, it decreased pulmonary capillary wedge AVP causes water retention, through the V2 receptor, pressure without affecting systemic vascular resistance, to maintain the blood pressure. However, AVP is respon- glomerular filtration rate, or renal blood flow and did not sible for cardiac hypertrophy and fibrosis at later stages affect plasma renin activity (25). Thus, the V2-receptor of heart failure. Therefore, the timing of the therapy with antagonists may offer a novel approach to remove excess AVP antagonists may be particularly important. AVP- water congestion in patients with heart failure. receptor antagonists are beneficial for the treatment of Unfortunately, the above clinical trials did not show hyponatremia in the setting of congestive heart failure. that a V2-receptor antagonist, particularly tolvaptan, However, these agents have not been shown to improve Role of Vasopressin in Heart Failure 5 short- or long-term morbidity or mortality in clinical of water metabolism in heart failure. Adv Exp Med Biol. studies. On the other hand, in experimental animal 1998;449:415–426. models of heart failure, AVP-receptor antagonists have 12 Chin MH, Goldman L. 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