Therapeutic Potential of Vasopressin-Receptor Antagonists in Heart Failure

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1 J Pharmacol Sci 124, (2014) Journal of Pharmacological Sciences The Japanese Pharmacological Society Current Perspective Therapeutic Potential of Vasopressin-Receptor Antagonists in Heart Failure Yasukatsu Izumi 1, *, Katsuyuki Miura 2, and Hiroshi Iwao 1 1 Department of Pharmacology, 2 Applied Pharmacology and Therapeutics, Osaka City University Medical School, Osaka , 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 oxytocin receptors and by AVP receptor subtypes: V 1a (mainly vascular), V 1b (pituitary), and V 2 (renal). Vaptans are orally and intravenously active nonpeptide vasopressin-receptor antagonists. Recently, subtype-selective nonpeptide vasopressin-receptor agonists have been developed. A selective V 1a -receptor antagonist, relcovaptan, has shown initial positive results in the treatment of Raynaud s disease, dysmenorrhea, and tocolysis. A selective V 1b -receptor antagonist, nelivaptan, has beneficial effects in the treatment of psychiatric disorders. Selective V 2 -receptor antagonists including mozavaptan, lixivaptan, satavaptan, and tolvaptan induce highly hypotonic diuresis without substantially affecting the excretion of electrolytes. A nonselective V 1a /V 2 -receptor antagonist, conivaptan, is used in the treatment for euvolaemic or hypervolemic hyponatremia. Recent basic and clinical studies have shown that AVP-receptor antagonists, especially V 2 -receptor antagonists, may have therapeutic potential for heart failure. This review presents current information about AVP and its antagonists. Keywords: arginine vasopressin, diuretic, heart failure, vasopressin receptor antagonist 1. Introduction *Corresponding author. izumi@msic.med.osaka-cu.ac.jp Published online in J-STAGE doi: /jphs.13R13CP Invited article The prevalence of heart failure has increased in the past several decades (1), and congestive heart failure has now emerged as a major public health hazard with grave implications. Rosamond et al. reported that 2.5% of the adult American population (approximately 5.3 million men and women) suffer from congestive heart failure, and the medical costs of heart failure in the United States are estimated at approximately $60 billion per year (2). Despite advanced medical care for patients with heart failure, the average 5-year survival is about 50% (3). Currently, various types of therapeutic agents are used for chronic heart failure as standard treatment, including angiotensin-converting enzyme inhibitors, angiotensinreceptor blockers, diuretics, b-adrenoceptor blockers, digitalis glycosides, and inotropic agents (4). Unfortunately, they are not enough to reduce mortality. Furthermore, therapeutic options in acute decompensated heart failure have not changed significantly over the past several decades despite advances in the management of chronic heart failure. Therefore, the discovery of novel agents is needed for successful treatment of heart failure. 2. Vasopressin in heart failure Arginine vasopressin (AVP) is secreted from the posterior pituitary in response to elevation in plasma osmolality and decreases in arterial pressure. AVP plays a key role in maintaining both volume homeostasis via osmotic AVP V 2 receptor expressed on the basolateral membranes of the renal collecting duct principal cells and vascular tone via nonosmotic AVP V 1a receptor expressed in vascular smooth muscle cells (5). 1

2 2 Y Izumi et al Fig. 1. Effects of individual subtypes of arginine vasopressin receptors. Three subtypes of AVP receptors have been identified so far, which belong to rhodopsin-like G-protein coupled receptors (6). The role of each AVP receptor subtype in the pathogenesis of heart failure is shown in Fig. 1. The V 1a receptor is found on vascular smooth muscle cells, hepatocytes, and platelets. Binding of AVP to the V 1a receptor activates Gq/phospholipase C-b, which results in an increase in intracellular calcium levels and activation of protein kinase C (5, 7), leading to vasoconstriction, platelet aggregation, and growth of the smooth muscle cells. The V 2 receptor is mainly located on the basolateral membrane of the collecting ducts in the renal medulla (6). Binding of AVP to the V 2 receptor activates adenylate cyclase via Gs protein, which leads to an increase in intracellular cyclic adenosine monophosphate (camp) (7). Elevation of intracellular camp facilitates translocation of aquaporin (AQP) channels from intracellular vesicles to the apical plasma membrane through activation of protein kinase A, leading to an increase in water permeability (8). The V 1b (V 3 ) receptor is found predominantly in the anterior pituitary, where it mediates adrenocorticotropin release. It is still unknown what role the V 1b receptor plays in heart failure. Previous studies have documented the presence of elevated AVP levels in patients with heart failure (9 10). In addition, an increase in AVP levels has been associated with increasing severity of heart failure (9). The increase in AVP levels results in impaired excretion of free water in patients with heart failure due to an increase in the number of AQP channels in the collecting duct (8). This results not only in abnormal water retention but also in hyponatremia (11). Water retention has detrimental effect in patients with heart failure because it leads to increased congestion, while hyponatremia is associated with increased mortality (12). Intravenous infusion of AVP in patients with heart failure increases systemic vascular resistance and pulmonary capillary wedge pressure, while it decreases stroke volume and cardiac output. These changes were thought to result from AVP-induced vasoconstriction mediated by the V 1a receptor because no association with alternation in blood pressure or heart rate was observed (13). Furthermore, stimulation of the V 1a receptor is associated with the development of cardiac hypertrophy in experimental animal models (14). Thus, chronic AVP stimulation could promote cardiac remodeling similarly to other neurohormonal systems. Elevated AVP levels activate the V 2 receptor, increase the expression of AQP channels, and cause water retention. As a result, preload and pulmonary capillary wedge pressure are increased. 3. Vasopressin-receptor antagonists in heart failure Selective AVP V 2 -receptor antagonists induce hypotonic diuresis without substantially affecting the excretion of electrolytes. and lixivaptan, V 2 - selective antagonists with K i V 2 :K i V 1a binding affinities of 29:1 and 100:1 in human cells, respectively, have been extensively studied in clinical trials and experimental animal models of heart failure. A small, randomized, placebo-controlled, crossover study showed a similar urine output in stable patients with heart failure with preserved renal function who received single doses of a loop diuretic (furosemide, 80 mg) or tolvaptan (30 mg) (15). There was no difference in the glomerular filtration rate between the two agents, although furosemide

3 Role of Vasopressin in Heart Failure 3 Table 1. Recent clinical trials using AVP antagonists in heart failure AVP Design, Setting, and Participants antagonist V 2-selective antagonist Lixivaptan Non-selective antagonist Conivaptan (intravenous) Randomized, double-blind, placebo-controlled, parallel-group, dose-ranging, phase 2 trial conducted at 45 centers in the United States and Argentina and enrolling 319 patients with left ventricular ejection fraction of less than 40% and hospitalized for heart failure with persistent signs and symptoms of systemic congestion despite standard therapy. Two identical prospective, randomized, double-blind, placebo-controlled trials at 359 sites in North America, South America, and Europe were conducted during the inpatient period of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With (EVEREST). A total of 4133 patients hospitalized with heart failure and congestion were studied. A total of 181 patients with advanced heart failure on standard therapy were randomized to double-blind treatment with tolvaptan at a single oral dose (15, 30, or 60 mg) or placebo. Patients with heart failure, systolic dysfunction, and signs of congestion were removed from baseline diuretic therapy and placed on a low-sodium diet. After a 2-day run-in period, 83 patients were randomized to placebo (n = 21), mono therapy 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. The effects of lixivaptan in 42 diuretic-requiring patients with mild-tomoderate heart failure in a randomized, double-blind, placebo-controlled, ascending single-dose study were examined. After overnight fluid deprivation, patients received single-blind placebo on day-1 and double-blind 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. In a double-blind, multicenter trial, 170 patients hospitalized for worsening heart failure and given standard therapy were randomly assigned to treatment with conivaptan (20-mg loading dose followed by 2 successive 24 h continuous infusions of 40, 80, or 120 mg/day) or placebo. Effect Increase in the net fluid loss, decrease in body weight, and improvement in the rate of worsening heart failure. No adverse effects such as changes in blood pressure, heart rate, or electrolytes. Improvement in body weight, peripheral edema, and patient-assessed dyspnea. No changes in morbidity or mortality. Increase in urine output and serum sodium levels in a dose-dependent manner. No changes in blood pressure, heart rate, systemic and pulmonary vascular resistance, or cardiac index. Reduction in body weight. Well tolerability. No changes in serum electrolytes, other laboratory values, or blood pressure. Increase in urine output in a dose-dependent manner. Increase in serum sodium level at higher doses. Improvement in urine output. Well tolerability. No changes in vital signs, electrolyte disturbances, or cardiac rhythm. Reference No increased urinary sodium and potassium excretion and decreased renal blood flow. Several studies have reported the effects of AVP-receptor antagonists on human and animal heart failure (16 17) Clinical trials (Table 1) The Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure (ACTIV in CHF) trial evaluated the short- and intermediate-term effects of tolvaptan in hospitalized patients with heart failure (18). In addition to the standard therapy, tolvaptan was administered to patients with the signs and symptoms of congestive heart failure and left ventricular ejection fraction of less than 40%. Compared with the standard-therapy group, the treatment group showed an increase in the net fluid loss resulting in decreased body weight. Although tolvaptan had no adverse effects such as changes in blood pressure, heart rate, or electrolytes, it did not improve the rate of worsening heart failure. The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with (EVEREST) evaluated the short- and long-term effects of tolvaptan added to standard therapy within 48 h of hospital admission for heart failure (19). A 60-day treatment with tolvaptan, in addition to standard therapy with diuretics, improved numerous signs and symptoms of heart failure without any serious side effects. An improvement in body weight, peripheral edema, and patient-assessed dyspnea was observed on days 1 and 7 of tolvaptan treatment, but the primary outcome variable, mortality, was not affected. The Effect of on Hemodynamic Parameters in Subjects with Heart Failure (ECLIPSE) trial investigated the effect of tolvaptan on hemodynamic parameters in patients with heart failure (20), including symptomatic heart failure and decreased ejection fraction. increased urine output and serum sodium levels in a dose-dependent manner. However, no significant differences were reported for the secondary endpoints of blood

4 4 Y Izumi et al pressure, heart rate, systemic and pulmonary vascular resistance, or cardiac index. Patients with heart failure, systolic dysfunction and signs of congestion (e.g., edema, rales), were removed from baseline diuretic therapy and placed on a lowsodium diet. And then, they were randomized to placebo, monotherapy with tolvaptan, monotherapy with furosemide, or both tolvaptan and furosemide once daily for 7 days (21). monotherapy without concomitant loop diuretic therapy reduced body weight when compared to placebo without adverse changes in serum electrolytes, during a sodium restricted diet while on background medications including angiotensin-converting enzyme inhibitors and b-blockers. A small study of stable patients with mild-to-moderate heart failure that examined the renal effects of lixivaptan showed that it increased urinary output in a dosedependent manner. The increase in urine volumes was accompanied by significant increases in solute-free water excretion, and serum sodium level was significantly increased at higher doses (22). These observations suggest that the lixivaptan may be a promising therapeutic agent for the treatment of heart failure. Trials on conivaptan showed that it significantly increased urine output and decreased body weight. Conivaptan, a nonselective V 1a /V 2 -receptor antagonist, is a combined V 1a - and V 2 -receptor antagonist with V 2 :V 1a binding affinity of 10:1. However, it failed to improve the clinical status of patients (23) Experimental animal models The beneficial effects of AVP-receptor antagonists in the treatment of heart failure have been demonstrated in experimental animal models. In dogs with heart failure induced by rapid right ventricular pacing, oral administration of OPC-21268, a selective V 1 -receptor antagonist, significantly improved cardiac output and renal function (24). On the other hand, mozavaptan, a selective V 2 -receptor antagonist, increased urinary output, serum sodium levels, as well as plasma renin and vasopressin levels, although it did not improve hemodynamic parameters. In a similar dog model, tolvaptan induced aquaresis with an increase in free water clearance, resulting in a significant increase in serum sodium concentrations and a decrease in cumulative water balance. Furthermore, it decreased pulmonary capillary wedge pressure without affecting systemic vascular resistance, glomerular filtration rate, or renal blood flow and did not affect plasma renin activity (25). Thus, the V 2 -receptor antagonists may offer a novel approach to remove excess water congestion in patients with heart failure. Unfortunately, the above clinical trials did not show that a V 2 -receptor antagonist, particularly tolvaptan, could improve cardiac function and mortality. Moreover, as most of the patients received concomitant medications, it is difficult to elucidate whether tolvaptan can independently improve the ejection fraction in patients with chronic heart failure. Recently, several studies have been published on the effects of tolvaptan in rat models of heart failure. The diuretic effects of tolvaptan were compared with those of furosemide in rats with chronic heart failure after autoimmune myocarditis (26). increased the plasma sodium concentration in a dose-dependent manner, while furosemide tended to decrease it. Importantly, plasma renin activity and aldosterone concentration were significantly increased by furosemide, while they were not affected by tolvaptan, suggesting that the latter has a potential benefit for the treatment of chronic heart failure with edematous conditions by removing excess water from the body without activating the renin-angiotensin-aldosterone system or causing serum electrolyte imbalance. In hypertensive rats with heart failure, chronic tolvaptan treatment had beneficial effects by preventing the progression of left ventricular dysfunction and renal injury (27). Furthermore, in rats with left ventricular dysfunction after myocardial infarction (MI), long-term tolvaptan therapy improved left ventricular ejection fraction and reduced MI-induced macrophage infiltration and interstitial fibrosis in the left ventricle. At the same time, tolvaptan was shown to attenuate MI-induced mrna expression of atrial and brain natriuretic peptides, which are reliable markers of heart failure (28), as well as monocyte chemotactic protein-1, transforming growth factor-b1, and endothelin-1 in the marginal infarct region (29). Furthermore, a 2-week treatment with tolvaptan improved the left ventricular ejection fraction and suppressed MI-induced left ventricular interstitial fibrosis and mineralocorticoid receptor expression in rats with acute heart failure after MI (30). These observations suggest that tolvaptan may have beneficial effects both on acute and chronic heart failure, which is partially mediated by the suppression of neurohumoral activation, the renin angiotensin aldosterone system, and inflammation. 4. Conclusions AVP causes water retention, through the V 2 receptor, to maintain the blood pressure. However, AVP is responsible for cardiac hypertrophy and fibrosis at later stages of heart failure. Therefore, the timing of the therapy with AVP antagonists may be particularly important. AVPreceptor antagonists are beneficial for the treatment of hyponatremia in the setting of congestive heart failure. However, these agents have not been shown to improve

5 Role of Vasopressin in Heart Failure 5 short- or long-term morbidity or mortality in clinical studies. On the other hand, in experimental animal models of heart failure, AVP-receptor antagonists have been shown to prevent cardiac remodeling. One of the reasons for the discrepancy between clinical trials and basic studies is that most of the clinical studies have focused on the effects of AVP antagonists in patients with heart failure who had been taking other diuretics and thus the results are difficult to interpret. Therefore, further studies are required to directly compare the effects of standard diuretic therapy with those of AVP antagonists in the clinical setting. Conflicts of Interest None declared. References 1 Fang J, Mensah GA, Croft JB, Keenan NL. Heart failure-related hospitalization in the U.S., 1979 to J Am Coll Cardiol. 2008;52: Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, et al. Heart disease and stroke statistics update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008;117:e25 e Croft JB, Giles WH, Pollard RA, Keenan NL, Casper ML, Anda RF. Heart failure survival among older adults in the United States: a poor prognosis for an emerging epidemic in the Medicare population. Arch Intern Med. 1999;159: Hunt SA, American College of C, American Heart Association Task Force on Practice G. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol. 2005;46: e1 e82. 5 Lee CR, Watkins ML, Patterson JH, Gattis W, O Connor CM, Gheorghiade M, et al. Vasopressin: a new target for the treatment of heart failure. Am Heart J. 2003;146: Carmichael MC, Kumar R. Molecular biology of vasopressin receptors. Semin Nephrol. 1994;14: Birnbaumer M. Vasopressin receptors. Trends Endocrinol Metab. 2000;11: Nielsen S, Kwon TH, Christensen BM, Promeneur D, Frokiaer J, Marples D. Physiology and pathophysiology of renal aquaporins. J Am Soc Nephrol. 1999;10: Francis GS, Benedict C, Johnstone DE, Kirlin PC, Nicklas J, Liang CS, et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation. 1990; 82: Goldsmith SR, Francis GS, Cowley AW Jr, Levine TB, Cohn JN. Increased plasma arginine vasopressin levels in patients with congestive heart failure. J Am Coll Cardiol. 1983;1: Schrier RW, Martin PY. Recent advances in the understanding of water metabolism in heart failure. Adv Exp Med Biol. 1998;449: Chin MH, Goldman L. Correlates of major complications or death in patients admitted to the hospital with congestive heart failure. Arch Intern Med. 1996;156: Goldsmith SR, Francis GS, Cowley AW Jr, Goldenberg IF, Cohn JN. Hemodynamic effects of infused arginine vasopressin in congestive heart failure. J Am Coll Cardiol. 1986;8: Nakamura Y, Haneda T, Osaki J, Miyata S, Kikuchi K. Hypertrophic growth of cultured neonatal rat heart cells mediated by vasopressin V(1A) receptor. Eur J Pharmacol. 2000;391: Costello-Boerrigter LC, Smith WB, Boerrigter G, Ouyang J, Zimmer CA, Orlandi C, et al. Vasopressin-2-receptor antagonism augments water excretion without changes in renal hemodynamics or sodium and potassium excretion in human heart failure. Am J Physiol Renal Physiol. 2006;290:F273 F Rehsia NS, Dhalla NS. Potential of endothelin-1 and vasopressin antagonists for the treatment of congestive heart failure. Heart Fail Rev. 2010;15: Valania G, Singh M, Slawsky MT. Targeting hyponatremia and hemodynamics in acute decompensated heart failure: is there a role for vasopressin antagonists? Curr Heart Fail Rep. 2011;8: Gheorghiade M, Gattis WA, O Connor CM, Adams KF Jr, Elkayam U, Barbagelata A, et al. Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial. JAMA. 2004;291: Gheorghiade M, Konstam MA, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, et al. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST Clinical Status Trials. JAMA. 2007;297: Udelson JE, Orlandi C, Ouyang J, Krasa H, Zimmer CA, Frivold G, et al. Acute hemodynamic effects of tolvaptan, a vasopressin V2 receptor blocker, in patients with symptomatic heart failure and systolic dysfunction: an international, multicenter, randomized, placebo-controlled trial. J Am Coll Cardiol. 2008;52: Udelson JE, Bilsker M, Hauptman PJ, Sequeira R, Thomas I, O Brien T, et al. A multicenter, randomized, double-blind, placebo-controlled study of tolvaptan monotherapy compared to furosemide and the combination of tolvaptan and furosemide in patients with heart failure and systolic dysfunction. J Card Fail. 2011;17: Abraham WT, Shamshirsaz AA, McFann K, Oren RM, Schrier RW. Aquaretic effect of lixivaptan, an oral, non-peptide, selective V2 receptor vasopressin antagonist, in New York Heart Association functional class II and III chronic heart failure patients. J Am Coll Cardiol. 2006;47: Goldsmith SR, Elkayam U, Haught WH, Barve A, He W. Efficacy and safety of the vasopressin V1A/V2-receptor antagonist conivaptan in acute decompensated heart failure: a dose-ranging pilot study. J Card Fail. 2008;14: Naitoh M, Suzuki H, Murakami M, Matsumoto A, Arakawa K, Ichihara A, et al. Effects of oral AVP receptor antagonists OPC and OPC on congestive heart failure in conscious dogs. Am J Physiol. 1994;267:H2245 H Onogawa T, Sakamoto Y, Nakamura S, Nakayama S, Fujiki

6 6 Y Izumi et al H, Yamamura Y. Effects of tolvaptan on systemic and renal hemodynamic function in dogs with congestive heart failure. Cardiovasc Drugs Ther. 2011;25 Suppl 1:S67 S Veeraveedu PT, Watanabe K, Ma M, Palaniyandi SS, Yamaguchi K, Kodama M, et al. Effects of V2-receptor antagonist tolvaptan and the loop diuretic furosemide in rats with heart failure. Biochem Pharmacol. 2008;75: Morooka H, Iwanaga Y, Tamaki Y, Takase T, Akahoshi Y, Nakano Y, et al. Chronic administration of oral vasopressin type 2 receptor antagonist tolvaptan exerts both myocardial and renal protective effects in rats with hypertensive heart failure. Circ Heart Fail. 2012;5: Kuwahara K, Nishikimi T, Nakao K. Transcriptional regulation of the fetal cardiac gene program. J Pharmacol Sci. 2012;119: Yamazaki T, Izumi Y, Nakamura Y, Yamashita N, Fujiki H, Osada-Oka M, et al. improves left ventricular dysfunction after myocardial infarction in rats. Circ Heart Fail. 2012;5: Yamazaki T, Nakamura Y, Shiota M, Osada-Oka M, Fujiki H, Hanatani A, et al. attenuates left ventricular fibrosis after acute myocardial infarction in rats. J Pharmacol Sci. 2013;123:58 66.