Cardiovascular Research

Cardiovascular Research 2001 51(3):391-402; doi:10.1016/S0008-6363(01)00315-7
© 2001 by European Society of Cardiology

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Copyright © 2000, European Society of Cardiology

Vasopressin V2 receptor antagonists

Lisa L. Wong^* and Joseph G. Verbalis

Department of Medicine, Division of Endocrinology and Metabolism, 232 Building D, Georgetown University School of Medicine, 4000 Reservoir Road NW, Washington, DC 20007, USA

^* Corresponding author. Tel.: +1-202-687-2818; fax: +1-202-687-2040

Received 2 April 2001; accepted 26 April 2001

	Abstract

Top Abstract 1 Introduction 2 Disorders associated with... 3 Treatment strategies:... 4 AVP receptor subtypes 5 AVP receptor antagonists 6 AVP V2 antagonists:... 7 AVP V2 antagonists:... 8 Vascular effects of... 9 AVP V2 antagonists:... 10 AVP V2 antagonists:... 11 Conclusions and future... References

 
Hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and disorders of water retention such as congestive heart failure and cirrhosis is a common problem encountered in the care of the medical patient. Thus far, available treatment modalities for disorders of excess arginine vasopressin (AVP) secretion or action have been suboptimal. The development of nonpeptide AVP V2 receptor antagonists represents a promising treatment option to directly antgonize the effects of elevated plasma AVP concentrations by increasing the water permeability of renal collecting tubules, thereby promoting excretion of retained water and normalizing hypoosmolar hyponatremia. In this review, SIADH and other water retaining disorders are briefly discussed, after which the published preclinical and clinical studies in the development of several nonpeptide AVP V2 receptor antagonists are summarized. The likely therapeutic indications and potential complications of these compounds, as well as their vascular effects, are also described.

KEYWORDS Hormones; Receptors; Vasoactive agents; Renal function; Heart failure

	1 Introduction

Top Abstract 1 Introduction 2 Disorders associated with... 3 Treatment strategies:... 4 AVP receptor subtypes 5 AVP receptor antagonists 6 AVP V2 antagonists:... 7 AVP V2 antagonists:... 8 Vascular effects of... 9 AVP V2 antagonists:... 10 AVP V2 antagonists:... 11 Conclusions and future... References

 
Hyponatremia remains the most common electrolyte abnormality encountered in hospitalized patients [1]. The incidence of hyponatremia depends both on the nature of the patient population studied and also on the criteria used to establish the diagnosis. Hospital incidences of 15–22% are common if hyponatremia is defined simply as a serum Na⁺<135 mmol/l, but only 1–4% of patients have a serum Na⁺130 [2]. Although most cases are mild, severe hyponatremia is associated with significant morbidity and mortality [3,4]. Euvolemic hyponatremia is the commonest type of hyponatremia in hospitalized patients [5], and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most frequently encountered cause of euvolemic hypoosmolality. In patients with SIADH, the secretion of arginine vasopressin (AVP) is not regulated physiologically, with the result that hypoosmolar conditions fail to suppress AVP secretion. To date, none of the present therapies for treating disorders of excess AVP secretion or action, leading to impaired water excretion, is optimal. One of the most exciting developments in the therapy of disorders of water metabolism is the development of selective nonpeptide AVP V2 receptor antagonists. These ‘aquaretic agents’ block the action of AVP in renal collecting duct cells, and thus promote water excretion. From a physiological perspective, an AVP V2 receptor antagonist should be the ideal agent to promote excretion of retained body water, and thereby normalize low plasma osmolality and serum Na⁺ concentration. These agents will therefore likely play an important future role in more effectively treating disorders of water retention such as SIADH, as well as edematous states with secondary water retention such as congestive heart failure and cirrhosis.

This article briefly summarizes SIADH and other water retaining disorders, and then reviews the development and current status of AVP V2 receptor antagonists and describes their potential therapeutic uses. For more details about specific compounds, as well as similar descriptions of antagonists to other AVP receptors, the reader is referred to several excellent recent reviews on this subject [6–13].

	2 Disorders associated with water retention

Top Abstract 1 Introduction 2 Disorders associated with... 3 Treatment strategies:... 4 AVP receptor subtypes 5 AVP receptor antagonists 6 AVP V2 antagonists:... 7 AVP V2 antagonists:... 8 Vascular effects of... 9 AVP V2 antagonists:... 10 AVP V2 antagonists:... 11 Conclusions and future... References

 
Arginine vasopressin, the ‘antidiuretic hormone’, is the major physiological regulator of renal free water excretion. The syndrome of inappropriate antidiuretic hormone secretion is characterized by hyponatremia secondary to increased total body water as a result of impaired renal free water excretion. Despite the development of hypoosmolality, patients with SIADH fail to suppress AVP secretion even when the plasma osmolality falls below the normal osmotic threshold for stimulating AVP secretion. Clinical criteria for the diagnosis of SIADH remain basically the same as when the syndrome was first described by Bartter and Schwartz in 1967 [14]. The patient must have true hypoosmolality with a urine osmolality that is greater than maximally dilute (i.e., >100 mOsm/kg H₂O) and an elevated urine Na⁺ excretion (i.e., >30 mmol/l). Clinical euvolemia must be demonstrated as well. Finally, because SIADH is to some degree a diagnosis of exclusion, there must be an absence of hypothyroidism, hypocortisolism, renal insufficiency and recent diuretic use. However, it is important to note that approximately 10–20% of patients who meet all of the above established criteria for SIADH do not have measurably elevated plasma AVP levels [15,16], leading some to propose use of the term SIAD (‘syndrome of inappropriate antidiuresis’) rather than SIADH to describe this entire group of disorders.

Hypoosmolar hyponatremia also occurs relatively frequently in advanced stages of congestive heart failure (CHF) and cirrhosis with ascites. In these disorders, a relatively decreased intravascular volume and/or pressure leads to water retention as a result of both decreased distal delivery of glomerular filtrate and secondarily elevated plasma AVP levels. For example, hyponatremic patients with advanced congestive heart failure often have inappropriately elevated plasma AVP levels, which fail to suppress completely even after acute water loading [17,18]. This occurs because in advanced heart failure, a low cardiac output causes an underfilling of the arterial vascular compartment, which unloads baroreceptors thereby activating the renin–angiotensin–aldosterone system, the sympathetic nervous system and AVP secretion in an effort to increase vascular resistance and enhance renal Na⁺ and water retention. Thus, despite a generalized hypervolemic edematous state, there is avid renal Na⁺ and water retention in an attempt to maintain the effective arterial blood volume [19].

Water retention with resultant hypoosmolar hyponatremia is also well documented in patients with advanced cirrhosis and ascites with edema. Many investigators have attempted to elucidate the pathophysiology of water retention in patients with advanced cirrhosis. Despite the obvious involvement of several different pathophysiological mechanisms in patients with cirrhosis and ascites, impaired free water excretion is correlated with inappropriately elevated plasma AVP levels [20]. Consequently, in both congestive heart failure and cirrhosis with ascites, nonosmotic stimulation of AVP release due to diminished effective arterial volume appears to mediate, in part, water retention and the development of hypoosmolar hyponatremia [21].

	3 Treatment strategies: disorders of hormone excess

Top Abstract 1 Introduction 2 Disorders associated with... 3 Treatment strategies:... 4 AVP receptor subtypes 5 AVP receptor antagonists 6 AVP V2 antagonists:... 7 AVP V2 antagonists:... 8 Vascular effects of... 9 AVP V2 antagonists:... 10 AVP V2 antagonists:... 11 Conclusions and future... References

 
SIADH is a disorder of relative AVP hormone excess, so it is rational to apply therapeutic strategies similar to those used for other endocrine disorders of hormone excess. These are: (1) to decrease the secretion of the hormone, (2) to decrease the effects of the hormone at its target tissues, and (3) to compensate for the effects produced by the excess hormone secretion. Although several drugs have been described that appear to decrease AVP secretion in some cases (e.g., diphenylhydantoin, opiates, ethanol), responses are erratic and often unpredictable. The second approach to treating hormone hypersecretion, namely to antagonize the end-organ effects of the hormone, has met with limited success. Until recently, pharmacological intervention for SIADH has been restricted to drugs with predominately post-receptor effects. The tetracycline derivative demeclocycline causes a nephrogenic form of diabetes insipidus, decreasing urine concentration even in the presence of high AVP levels. However, demeclocycline can cause nephrotoxicity, especially in patients with cirrhosis, although in most cases this has been reversible. Other agents, such as lithium carbonate, have similar post-receptor effects but are less desirable because of inconsistent results and significantly greater side effects. Because of the problems associated with these therapies, the most frequently employed strategy has been to compensate for the effects of excess AVP secretion by restricting free water intake. Reduction of fluid intake to levels less than insensible plus kidney free water losses induces a negative water balance with subsequent increases in plasma osmolality and serum Na⁺ concentration. Although fluid restriction therefore can effectively counteract the effect of excess AVP secretion, it does not directly inhibit the excess hormone secretion or its actions. Furthermore, for many patients, long-term fluid restriction can be uncomfortable, difficult to maintain, and relatively ineffective.

With the cloning and sequencing of the receptors to which AVP binds, agents that can more directly antagonize effects of the hormone at its receptors have now been developed. By virtue of these actions, AVP V2 receptor antagonists are promising agents that can block the action of AVP at the AVP V2 receptors in the collecting ducts of the kidney. These agents therefore have the potential to increase free water clearance in states of AVP excess, regardless of the cause of the AVP hypersecretion.

	4 AVP receptor subtypes

Top Abstract 1 Introduction 2 Disorders associated with... 3 Treatment strategies:... 4 AVP receptor subtypes 5 AVP receptor antagonists 6 AVP V2 antagonists:... 7 AVP V2 antagonists:... 8 Vascular effects of... 9 AVP V2 antagonists:... 10 AVP V2 antagonists:... 11 Conclusions and future... References

 
Before describing the development of AVP receptor antagonists, it is necessary first to briefly summarize what is known about the different AVP receptor types. AVP acts as an antidiuretic hormone at physiological plasma concentrations and as a vasoconstrictive pressor hormone only at higher plasma levels. All vasopressin receptor subtypes belong to the seven transmembrane domain, G protein-coupled receptor super family. Three known receptor subtypes mediate the actions of AVP. They are classified according to the second messenger system to which they are coupled. The V1a and V1b (also known as V3) receptors are linked to the phosphoinositol signaling pathway with intracellular calcium acting as the second messenger. In contrast, the V2 receptors are linked to the adenylate cyclase signaling pathway with intracellular cAMP acting as the second messenger [22]. The V1a receptor subtype is ubiquitous and is present on vascular smooth muscle cells, hepatocytes and platelets where it mediates vascular constriction, glycogenolysis and platelet aggregation, respectively. V1b, or V3, receptors are found predominately in the anterior pituitary where they mediate adrenocorticotropin release.

V2 receptors are present predominately in the kidney collecting tubules where they mediate free water reabsorption. In addition, there is now evidence indicating the presence of extrarenal V2 receptors on endothelial cells that may be involved in von Willebrand factor secretion [23,24].

Activation of the vasopressin V2 receptor, mainly present in renal collecting ducts, leads to an increase in intracellular cAMP by stimulating adenylate cyclase activity through G_s protein. This, in turn, regulates renal free water excretion by shuttling aquaporin-2 (AQP2) water channels from intracellular vesicles into the apical plasma membrane of the renal collecting duct cells, thereby increasing water permeability of the membrane and producing an antidiuresis [25].

	5 AVP receptor antagonists

Top Abstract 1 Introduction 2 Disorders associated with... 3 Treatment strategies:... 4 AVP receptor subtypes 5 AVP receptor antagonists 6 AVP V2 antagonists:... 7 AVP V2 antagonists:... 8 Vascular effects of... 9 AVP V2 antagonists:... 10 AVP V2 antagonists:... 11 Conclusions and future... References

 
Manning and Sawyer first designed peptide antagonists of both the antidiuretic and the pressor responses to AVP in the 1970s. They synthesized and tested more than 50 vasopressin analogs before finally finding a combination of modifications that produced the first effective antagonist of the antidiuretic response in vivo. They started by modifying the highly specific and potent antidiuretic peptide desmopressin, a selective V2 receptor agonist [26]. Later, they also discovered that the characteristic ring structure of AVP is not required for binding of synthetic peptides to AVP receptors. Thus, linear peptides that are easier to synthesize than cyclic peptides were developed to also block the V2 receptor responses to AVP [27]. However, despite demonstrating potent V2 receptor antagonism in animals, many V2 receptor antagonists tested in humans have paradoxically exhibited weak V2 receptor agonism rather than antagonizing the V2 receptor effects of AVP. Subsequent studies have suggested that this marked species difference was likely due to differences in kidney prostaglandin secretion in humans as compared to other species [28]. The challenge was therefore to synthesize an analog of the parent molecule that would retain its ability to bind to AVP V2 receptors, but not activate the adenylyl cyclase signal transduction cascade [27].

5.1 Peptide antagonists
Several cyclic and linear peptide AVP receptor antagonists derived from AVP that express various degrees of selectivity for AVP receptor subtypes have been designed. Although these peptide antagonists are relatively potent in animals [29] and have been available for over 20 years, their use in the therapy of water retaining disorders and clinical investigation has been essentially nonexistent. This is due primarily to the marked species-differences described above with resultant partial agonist actions in humans [30], and also to their poor oral bioavailability and short biological half-life.

5.2 Nonpeptide antagonists (Table 1)
In 1992 Yamamura et al. characterized the first nonpeptide V2 receptor antagonist, OPC-31260 [31], which was discovered via a series of structural conversions of OPC-21268, an AVP V1a receptor antagonist discovered previously via functional screening strategies. Of most importance, this and similar compounds have been found to be devoid of V2 receptor agonist effects in humans. Additional advantages of the nonpeptide antagonists are that whereas peptide antagonists were limited to parenteral use, nonpeptide antagonists are generally orally bioavailable, as well as having a longer half-life than most peptides. However, since nonpeptide antagonists are generally highly lipophilic, one potential disadvantage of these compounds is their penetration across the blood–brain barrier with possible central nervous system side effects.

View this table: [in this window] [in a new window]   Table 1 AVP receptor antagonists used in past or current clinical trials

 

	6 AVP V2 antagonists: preclinical studies (Table 2)

Top Abstract 1 Introduction 2 Disorders associated with... 3 Treatment strategies:... 4 AVP receptor subtypes 5 AVP receptor antagonists 6 AVP V2 antagonists:... 7 AVP V2 antagonists:... 8 Vascular effects of... 9 AVP V2 antagonists:... 10 AVP V2 antagonists:... 11 Conclusions and future... References

 
In vitro studies have documented that nonpeptide V2 receptor antagonists inhibit binding of AVP to V2 receptors. OPC-31260 antagonized the binding of AVP to V2 receptors in rat kidney plasma membranes [31]. In 1996, Serradeil-Le Gal et al. characterized another orally active, nonpeptide AVP V2 receptor antagonist, SR-121463 [32]. This compound demonstrated highly competitive and selective affinity for V2 receptors in rat, bovine and human kidneys, and in binding experiments SR-121463 was found to inhibit [³H]AVP labeling to rat, bovine and human kidney membranes. Radioligand displacement studies showed a relative V2:V1 selectivity of over 7000-fold in rat and 100-fold in human tissues. SR-121463 also potently antagonized AVP-stimulated adenylyl cyclase activity. VPA-985, another potent selective nonpeptide V2 receptor antagonist, similarly inhibited binding of AVP to native V2 receptors in membrane isolates from rat and dog renal medulla [33]. In 1997, Tahara et al. characterized a nonpeptide combined V1a and V2 receptor antagonist, YM-087. This agent demonstrated a high affinity for V1a receptors from rat liver and V2 receptors from rat kidney. It interacted reversibly and competitively with both receptor types, potently blocked AVP-induced cAMP production in cultured renal epithelium cells [34], and dose dependently displaced a V2 receptor radioligand at V2 receptors in rat kidney medullary membranes [35].

View this table: [in this window] [in a new window]   Table 2 Published animal studies using AVP V2 receptor antagonists

 
Conditions of extracellular fluid expansion such as congestive heart failure and liver cirrhosis, are associated with increased kidney expression of the AVP-stimulated water channel, AQP2. Conversely, a reduction in kidney AQP2 levels have been found in several acquired forms of nephrogenic diabetes insipidus [25,36]. OPC-31260 caused a rapid and significant reduction in AQP2 mRNA expression in rat kidney [37], and also significantly diminished the increased expression of AQP2 mRNA in collecting ducts of both rats with experimentally induced SIADH and cirrhosis [38]. These studies therefore have confirmed that modulation of AQP2 transcription in the kidney is regulated via AVP V2 receptor signaling pathways.

Numerous in vivo animal studies have demonstrated the unmistakable aquaretic effect (i.e., the ability to produce a water diuresis) of nonpeptide AVP V2 receptor antagonists [31,33,35,39–42]. Nonpeptide antagonists have been shown to produce a dose-dependent aquaresis in both dehydrated [34] and normally hydrated animals [32,43]. Seven days of treatment with oral YM-087 achieved a dose-dependent aquaresis in rats without affecting blood pressure or causing tachyphylaxis [35]. SR-121463 similarly induced an effective, dose-dependent aquaresis after intravenous or oral administration in rats, and it had at least 10 times more potent oral efficacy than OPC-31260 [32]. In addition, nonpeptide AVP V2 receptor antagonists have been shown to markedly increase free water excretion in animals with water retaining states such as experimental cirrhosis, SIADH [44] and CHF [45,46]. Studies in which SIADH was produced in rats with administration of the AVP V2 receptor agonist desmopressin revealed that OPC-31260 promptly induced a marked water diuresis, as evidenced by an increase in urinary volume, a fall in urinary osmolality and normalization of serum Na⁺ concentrations [38,47]. In AVP-deficient Brattleboro rats, OPC-31260 completely blocked the action of administered desmopressin [48].

In dogs with congestive heart failure produced by rapid ventricular pacing, OPC-31260 induced marked water diuresis that resulted in significant increases in serum Na⁺ concentrations and plasma AVP levels, but did not produce either hemodynamic improvement or decompensation [49]. A similar aquaretic effect was seen in post infarction (induced by coronary artery ligation) heart failure in rats treated with the antagonist for as long as 6 months [50]. However, in dogs with pacing-induced congestive heart failure, the combined V1a and V2 AVP receptor antagonist YM-087 not only increased free water clearance, but also increased cardiac output and decreased left ventricular end-diastolic pressure and total peripheral vascular resistance [51].

Animal studies have also shown that nonpeptide vasopressin V2 receptor antagonists are ‘aquaretic agents,’ selectively increasing free water excretion without inducing a significant solute diuresis, in contradistinction to ‘saluretic agents’, such as furosemide, which increase urinary NaCl excretion to a much greater extent [31]. Yatsu et al. demonstrated that YM-087 increased free water excretion without increasing urinary excretion of electrolytes in the normally hydrated conscious dog [43]. In comparing the nonpeptide V2 receptor antagonist OPC-41061, which was derived from OPC-31260, with furosemide in conscious rats, OPC-41061 was found to exert an aquaretic effect, whereas equivalent diuretic doses of furosemide also exerted a natriuretic effect [52]. As a result, OPC-41061 dose-dependently elevated the serum Na⁺ concentration while furosemide tended to decrease it.

Brooks et al. compared OPC-31260 with opioid agonists, which are known inhibitors of vasopressin secretion, in conscious hydropenic dogs. Although both agents increased urine flow and decreased urine osmolality, the opioid agonists led to Na⁺ retention, tachycardia and central nervous system side effects. In contrast, OPC-31260 caused a more consistent increased free water clearance without changes in Na⁺ excretion, heart rate or central nervous system effects [53].

	7 AVP V2 antagonists: clinical studies (Table 3)

Top Abstract 1 Introduction 2 Disorders associated with... 3 Treatment strategies:... 4 AVP receptor subtypes 5 AVP receptor antagonists 6 AVP V2 antagonists:... 7 AVP V2 antagonists:... 8 Vascular effects of... 9 AVP V2 antagonists:... 10 AVP V2 antagonists:... 11 Conclusions and future... References

 
Phase I type trials have established the relative safety of many nonpeptide V2 receptor antagonists in humans. In 1993, Ohnishi et al. administered intravenous OPC-31260 to normally hydrated normal volunteers and demonstrated that the agent dose-dependently induced a water diuresis without altering urinary Na⁺ or K⁺ excretion, or blood pressure. In comparing its effect to furosemide, the diuretic effect was almost equipotent to furosemide, but furosemide induced a natriuresis acutely, whereas OPC-31260 only caused a slight increase in urinary Na⁺, similar to the results of previous animal studies. No undesirable signs or symptoms or changes in laboratory safety parameters were observed [54]. In a subsequent study, Ohnishi et al. administered a single dose of oral OPC-31260 in six dose steps to six normal subjects and compared them to 12 placebo-controlled subjects. A dose-dependent aquaresis was produced without altering either the blood pressure or the heart rate, and there were no adverse effects except for the expected mild to moderate thirst that was tolerated well by all subjects [55]. In 1999, Burnier et al. demonstrated that a single dose of YM-087 induced aquaresis in six healthy subjects. YM-087 was similarly well tolerated without significant adverse clinical or biochemical events, or changes in blood pressure or heart rate. All subjects except one again reported the development of increased thirst [56].

View this table: [in this window] [in a new window]   Table 3 Published clinical studies using AVP V2 receptor antagonists

 
Since V2 receptor antagonists will likely be most advantageous in conditions of water retention due to inappropriately elevated plasma AVP levels, such as SIADH, it was of particular importance to investigate the effects of these agents in hydropenic normal subjects who had increased endogenous AVP secretion and maximally concentrated urine. Shimizu et al. demonstrated that intravenous OPC-31260 caused a dose-dependent aquaresis in normal human subjects under conditions of water restriction. Even in this mildly volume contracted group of subjects, no significant changes in blood pressure or heart rate, or other adverse effects, were reported [57]. These and other clinical studies have therefore demonstrated the ability to safely induce free water excretion using nonpeptide vasopressin V2 receptor antagonists in both normally hydrated and mildly volume depleted human subjects.

Several Phase II type trials have also been conducted in patients with water retaining disorders, and they have similarly confirmed the efficacy of nonpeptide V2 receptor antagonists in human patients with disorders of water retention. In 1997, Saito et al. administered OPC-31260 intravenously to 11 patients diagnosed as having chronic SIADH. A single dose of this agent increased urinary volume and free water clearance in a dose-dependent manner. As a result, the aquaretic effect caused a significant increase in serum Na⁺ concentrations by approximately 3 mmol/l after 4 h without changes in urinary solute excretion [58]. Besides efficacy in patients with SIADH, the nonpeptide antagonists also appear to produce effective aquaresis in patients with liver cirrhosis. A single oral dose of OPC-31260 administered to eight patients with biopsy-proven cirrhosis with ascites or peripheral edema caused increased urine excretion with a lowered urinary osmolality. However, these aquaretic responses were only approximately half the responses that were observed with similar doses in healthy subjects [59]. Finally, efficacy has also been demonstrated in patients with congestive heart failure. Oral VPA-985 administration in 21 patients with chronic NYHA class II or III heart failure significantly increased free water clearance and decreased urinary osmolality as compared to placebo. VPA-985 also significantly decreased urinary AQP-2 in a dose-dependent manner [60]. A recent randomized, double-blind placebo-controlled multicenter trial of VPA-985 administered for up to 7 days in 112 patients (61 with liver cirrhosis and ascites, 14 with CHF, and 31 with SIADH) resulted in significant increases in serum Na⁺ concentrations and decreases in urine osmolality [9]. Both plasma osmolality and free water clearance increased as well. These and other studies have therefore shown the efficacy of nonpeptide vasopressin V2 receptor antagonists to reverse impaired free water excretion in patients with SIADH, cirrhosis and congestive heart failure.

Currently, several of the antagonists discussed above are already in, or are beginning, larger Phase III efficacy and safety trials. However, in a disturbing trend, further clinical development of some of these agents for treating disorders of water retention has been halted, apparently because of marketing concerns regarding the potentially limited number of patients who would be candidates for their use. It will indeed be unfortunate if such financial concerns keep agents that are safe and efficacious from being utilized for a group of patients for whom therapies are limited and often ineffective.

	8 Vascular effects of AVP V2 antagonists

Top Abstract 1 Introduction 2 Disorders associated with... 3 Treatment strategies:... 4 AVP receptor subtypes 5 AVP receptor antagonists 6 AVP V2 antagonists:... 7 AVP V2 antagonists:... 8 Vascular effects of... 9 AVP V2 antagonists:... 10 AVP V2 antagonists:... 11 Conclusions and future... References

 
Although V2 receptors have been clearly characterized in renal tubular cells, there has been indirect pharmacological evidence suggesting that extrarenal V2 or ‘V2 like’ receptors might exist in the peripheral vasculature as well. This has recently been confirmed with the finding that endogenous AVP V2 receptors are expressed in human lung microvascular endothelial cells [24]. However, the role of V2 receptors in vascular function is still incompletely understood. Results from studies using nonpeptide AVP antagonists have been confusing, suggesting both vasoconstrictor and vasopressor actions mediated by ‘V2-like’ receptors, and require cautious interpretation due to the variable and complex nature of the vasopressin system and the possibility of overlapping effects of the antagonists on different AVP receptor subtypes. AVP V2 receptor-mediated vasoconstriction has been suggested by in vitro studies, but upon closer analysis it became apparent that the vasodilatory effects produced by AVP V2 antagonists were most likely mediated via AVP V1a receptor antagonism. AVP-induced vasoconstriction of isolated simian femoral arteries was not significantly modified by OPC-21268, a V1a receptor antagonist, but was markedly inhibited by the V2 antagonist OPC-31260. These results were initially interpreted as evidence of V2 or ‘V2 like’ receptors mediating the AVP-induced vasoconstriction [61]. However, since then the supposedly ‘selective’ AVP V2 receptor antagonist, OPC-31260, has been characterized further to possess partial V1a as well as V2 receptor antagonist activity [62]. Thus, the observed inhibition of AVP-induced contraction was likely mediated via V1a receptor blockade produced by the V2 antagonist. Similarly, in rat caudal arteries, VPA-985 has been shown to shift the concentration–response curves of AVP-induced contraction to the right in a dose-dependent manner due to its V1a receptor antagonist effects [33], and OPC-31260 inhibited vasopressin-induced contraction in the human internal mammary artery through its actions as a V1a receptor antagonist [62]. In addition, in the human isolated coronary artery, both OPC-31260 and OPC-21268 acted as antagonists of AVP-induced vascular contraction, although they were less potent antagonists than the V1a receptor antagonist, SR-49059, and the antagonist potency order corresponded to the affinity of the various antagonists for the AVP V1a receptor [63]. In all these instances, it is therefore likely that many of the effects of different AVP V2 antagonists to block AVP-induced vasoconstriction can, for the most part, be explained by their affinity for the AVP V1a receptor as well.

Many more studies have suggested vasodilatory effects of AVP that may be mediated through ‘V2 like’ vascular receptors. Intrarenal infusion of AVP in dogs caused renal vasodilation in the presence of the V1a antagonist OPC-21268, and this vasodilation was inhibited by simultaneous pretreatment with OPC-31260 [64]. The selective AVP V2 receptor agonist desmopressin was found to induce relaxation of isolated rat aortic strips precontracted with norepinephrine, which was endothelium dependent and was blocked by inhibitors of nitric oxide production [65]. Because this effect could be antagonized by both peptide and non-peptide AVP V1a receptor antagonists but not by two peptide V2 antagonists, these results suggested that desmopressin-induced vasorelaxation may be mediated by an endothelial V1a-like receptor subtype with affinity for V2 ligands. Similar recent studies in aortic rings have demonstrated antagonism of desmopressin vasorelaxing activity by both V2 (SR-121463A) and V1a (SR-49059) antagonists, suggesting that desmopressin-induced vasorelaxation may be mediated by an endothelial receptor subtype sharing both V1a and V2 pharmacological profiles [66]. However, in vivo studies in humans have shown that infusion of AVP into the brachial artery of humans at high doses causes vasodilation [67], but this effect is lost in patients with nephrogenic diabetes insipidus and documented mutations of the AVP V2 receptor, suggesting that AVP-mediated vasorelaxation is, in fact, mediated by classical V2 receptors [68].

Regardless of the substantial data implicating V2 receptors in the vasodilatory effects of AVP, likely via regional stimulation of endothelial release of nitric oxide, the physiological significance of the ability of some nonpeptide AVP V2 antagonists to antagonize AVP-induced vasodilation in selected vascular beds is less clear. Some studies [35,48], though not all [58] have demonstrated increased vasopressin levels with V2 receptor blockade, causing some concern about the consequences of such an increase on renal or hemodynamic effects. Although vascular effects of V2-like receptors have been suggested by the studies described above, there has been lack of evidence to support a physiologically significant effect of AVP V2 antagonists on total peripheral resistance or blood pressure in vivo. Animal studies have repeatedly shown that nonpeptide AVP V2 antagonists do not alter systemic arterial pressure [33,35,39,40,49,69]. Likewise, these compounds have not been found to cause significant hemodynamic effects in human studies to date [58].

The hemodynamic role of AVP in heart failure through its vasoconstrictor actions on V1a receptors have also been controversial. Plasma AVP levels have been reported to be elevated in some patients with CHF and in some patients with hypertension. However, plasma AVP levels in CHF are very variable. A vasodilator response to a V1a receptor antagonist was observed in only a small proportion of patients with heart failure whose AVP levels were very high [46,70]. However, intravenous YM087 significantly increased cardiac output and decreased left ventricular end-diastolic pressure and total peripheral resistance in dogs with pacing-induced CHF [51], and studies in dogs with experimental congestive heart failure have demonstrated improved hemodynamic effects with a combination of V1a (OPC-21268) and V2 (OPC-31260) antagonists more so than with either antagonist used separately [49]. Whether chronic V2 receptor blockade could cause an increase in peripheral vascular resistance and augment afterload because of increases in plasma AVP levels acting on V1a receptors is not known. If this proves to be true, then treatment of such patients with a combined V2 and V1a receptor antagonist such as YM-087 may prove to be advantageous [7]. Thus, the development and use of nonpeptide AVP V2 antagonists have assisted investigators in characterizing possible extrarenal V2 or ‘V2 like’ receptors and have begun to define some of the unexplored physiological roles of these receptors, but the clinical implications of such effects are of questionable physiological significance for the therapeutic use of AVP V2 antagonists and will require further investigation to fully understand.

	9 AVP V2 antagonists: potential therapeutic indications

Top Abstract 1 Introduction 2 Disorders associated with... 3 Treatment strategies:... 4 AVP receptor subtypes 5 AVP receptor antagonists 6 AVP V2 antagonists:... 7 AVP V2 antagonists:... 8 Vascular effects of... 9 AVP V2 antagonists:... 10 AVP V2 antagonists:... 11 Conclusions and future... References

 
The most certain indication for the clinical use of vasopressin V2 receptor antagonists will be SIADH. Although there are many different etiologies for SIADH, it seems likely that AVP V2 receptor antagonists will prove to be efficacious regardless of the underlying pathophysiology of the disease. Patients with ectopic sources of inappropriate vasopressin secretion, such as small cell lung cancer and other tumor-related SIADH, should benefit from inhibiting the effects of vasopressin at the renal V2 receptor. Successful treatment of such cases will allow liberalization of fluid restriction, as well as decreasing the morbidity associated with the development of hypoosmolar hyponatremia. Another likely subset of patients with SIADH who should benefit from AVP V2 receptor antagonist therapy are those with CNS disorders causing hypersecretion of vasopressin. Since these patients are often at high risk for confusion, falls and seizure activity, raising serum Na⁺ levels with an AVP V2 receptor antagonist would clearly be advantageous. Drug-induced SIADH is also a potential indication for V2 receptor antagonist therapy. Many patients are unable to simply discontinue medications such as selective serotonin reuptake inhibitors, carbamazepine or phenothiazines in order to reverse the drug-induced SIADH. With the addition of an AVP V2 receptor antagonist, many such patients may be able to continue taking necessary medications despite side effects of stimulating the release of AVP or a potentiation of the effect of AVP on the kidneys.

Other likely indications for AVP V2 receptor antagonists include edema-forming states with diminished effective arterial circulation and secondarily inappropriately elevated AVP levels, such as advanced congestive heart failure and cirrhosis. Patients with CHF often do not correct hypoosmolar hyponatremia with conventional loop diuretic therapy. However, reversing impaired free water excretion with AVP V2 receptor antagonists could normalize dilutional hyponatremia in congestive heart failure patients. V2 receptor antagonists will likely prove to be superior to conventional diuretics in this setting, since they can induce free water diuresis without solute diuresis. AVP V2 receptor antagonist therapy may also be suitable in patients with cirrhosis, intractable ascites and peripheral edema, who are often ineffectively treated with aldosterone antagonists and β-blockers. In both congestive heart failure and cirrhosis with ascites, these agents may therefore improve quality of life by allowing increased fluid intake, and decrease morbidity by preventing or correcting hypoosmolality.

In addition to the above likely indications for AVP V2 antagonists, there are several possible additional indications for the use of such agents. These include: (1) prompt correction of symptomatic hyponatremia, (2) diagnosis of vasopressin-mediated hyponatremia, and (3) combination therapy with diuretic agents. Cases of acute hyponatremia (generally defined as 48 h in duration) are usually symptomatic if the hyponatremia is severe (i.e., 120 mmol/l). These patients are at greatest risk from neurological complications from the hyponatremia itself and should be corrected to higher levels of serum Na⁺ promptly [71]. Standard therapy of such patients is currently administration of graded amounts of hypertonic (3%) NaCl [72], but titrated doses of AVP V2 receptor antagonists may prove effective at inducing a prompt but limited free water diuresis to increase serum Na⁺ concentrations and prevent neurological complications from hyponatremic encephalopathy.

Although the majority of patients with SIADH have measurably elevated plasma AVP levels, in some cases the diagnosis of AVP-mediated hyponatremia is unclear. These patients clearly demonstrate excessive free water retention and meet all of the classical criteria for a diagnosis of SIADH, but plasma AVP levels do not appear to be inappropriately elevated, and in some cases are actually unmeasurable [15]. This may be due to the presence of another circulating antidiuretic substance, or to increased AVP V2 receptor sensitivity to very low AVP levels [16]. In these cases, AVP V2 receptor antagonists would be ideal agents not only for diagnosis, but also for treatment. Response to treatment with an AVP V2 receptor antagonist would confirm activation of the V2 receptor as a cause of this disorder versus post-receptor effects (e.g., direct effects on AQP-2 water channel insertion into the apical membranes of collecting duct cells). One such case has recently been reported in which an AVP V2 antagonist caused a free water diuresis despite non-elevated plasma AVP levels [73].

Finally, AVP V2 receptor antagonist therapy could be a valuable adjunct to other diuretic agents, such as furosemide, in the treatment of edematous states. Obviously a solute diuresis in the form of natriuresis is desirable in patients with edema-forming disorders. However, in many cases a combination of aquaretic and diuretic therapies may prove superior to diuretics alone, by virtue of producing a greater free water diuresis, avoiding hyponatremia, and requiring lesser potassium replacement therapy by virtue of lower total diuretic requirements.

	10 AVP V2 antagonists: potential complications

Top Abstract 1 Introduction 2 Disorders associated with... 3 Treatment strategies:... 4 AVP receptor subtypes 5 AVP receptor antagonists 6 AVP V2 antagonists:... 7 AVP V2 antagonists:... 8 Vascular effects of... 9 AVP V2 antagonists:... 10 AVP V2 antagonists:... 11 Conclusions and future... References

 
The known potential complications of AVP V2 receptor antagonist therapy include central pontine myelinolysis due to an overly rapid correction of hyponatremia and inappropriate use in hypovolemic hyponatremia. Too rapid a correction of severe hyponatremia can produce pontine and extrapontine myelinolysis, a brain demyelinating disease that can cause substantial neurological morbidity and mortality. Demyelination can occurs independently of the method used to correct hyponatremia in both experimental animals [74] and clinical studies, and patients corrected too rapidly with AVP receptor antagonists will also be at increased risk for brain demyelination [75]. Although correction of plasma Na⁺ in patients with acute hyponatremia carries little, if any, risk of demyelination, patients with more chronic hyponatremia (<48 h in duration) can develop demyelination after rapid correction because of greater degrees of brain volume regulation through electrolyte and osmolyte losses. There is no indication to correct these patients rapidly, regardless of the initial plasma Na⁺ concentration. The same guidelines for treatment of hyponatremia should be followed when using AVP receptor antagonists as for other correction therapies such as hypertonic saline administration. In all cases, the rate of correction should be determined by weighing risks of hyponatremia against those associated with rapid correction. This generally can be estimated by the patient's duration of hyponatremia and the presence or absence of neurological symptoms [76]. Although acute, symptomatic hyponatremia must be corrected quickly, in most patients a reasonable approach is controlled and limited correction that stays within the parameters shown to be safe from previous clinical studies. This will likely be achievable by using titrated doses of AVP V2 antagonists with careful monitoring of the serum Na⁺ concentration during the active phase of the correction.

Finally, AVP V2 receptor antagonists should only be used in euvolemic or hypervolemic hyponatremic states (i.e., SIADH, congestive heart failure, cirrhosis with ascites). It should be obvious that use of AVP V2 receptor antagonists in hypovolemic hyponatremia will aggravate underlying hypovolemia and potentially lead to complications of dehydration and hypotension due to the increased free water excretion induced by these agents in the presence of hypovolemia. Special caution should be exercised in patients with cirrhosis who are at increased risk for intravascular volume depletion and renal failure. A careful assessment of the patients’ clinical volume status will therefore be essential before initiating treatment with an AVP V2 receptor antagonist. Any history consistent with volume depletion (e.g., thiazide diuretic use) or any clinical manifestations of disorders associated with volume depletion (e.g., primary adrenal insufficiency) are contraindications to use of either an aquaretic or diuretic agent. Similarly, a low urinary Na⁺ concentration (i.e., <30 mmol/l) should alert clinicians to the likelihood of underlying hypovolemia. These patients should be treated initially with isotonic saline to expand blood and extracellular volume; only if hypoosmolar hyponatremia persists after correction to a euvolemic state can an AVP V2 receptor antagonist then be safely employed.

In using these agents clinically, investigators and clinicians must also be attentive to potential unknown complications such as CNS side effects from blood–brain barrier penetration of lipophilic nonpeptide vasopressin V2 receptor antagonists, although to date these have not been reported. Finally, with the introduction of any new class of drugs, we must always be vigilant for unexpected toxicities, particularly interactions with other drugs, or with their metabolism via the cytochrome P₄₅₀ system.

	11 Conclusions and future projections

Top Abstract 1 Introduction 2 Disorders associated with... 3 Treatment strategies:... 4 AVP receptor subtypes 5 AVP receptor antagonists 6 AVP V2 antagonists:... 7 AVP V2 antagonists:... 8 Vascular effects of... 9 AVP V2 antagonists:... 10 AVP V2 antagonists:... 11 Conclusions and future... References

 
It appears likely that we are poised to begin a new era in both the evaluation and the treatment of patients with euvolemic or hypervolemic hyponatremia. Nonpeptide AVP V2 receptor antagonists are clearly efficacious in producing a free water diuresis in humans. Short-term studies in patients with SIADH and CHF suggest that such agents will allow normalization of plasma osmolality with less required restriction of fluid intakes. The resultant therapy of patients with chronic hyponatremia will very likely be much simpler and more effective than at the present time. However, the safe use of AVP V2 receptor antagonists will require avoidance of their use in hypovolemic patients and caution with regard to the rate of correction of hyponatremia induced. Appropriate dosing and monitoring should allow successful adherence to the same guidelines for limited controlled correction that apply to other correction methods, and single doses of such agents may prove to be the ideal method for achieving small rapid corrections of plasma Na⁺ that will satisfactorily reverse hyponatremic encephalopathy without producing excessive corrections with their subsequent neurological complications. The numbers of patients potentially benefiting from such agents is difficult to project at this time, but since hyponatremia remains the most common electrolyte disorder of hospitalized patients, and is particularly prevalent in the elderly, it seems likely that these agents will represent an important addition to our therapeutic armamentarium for treating disorders of water retention once they are shown to be safe in ongoing long-term clinical studies.

Time for primary review 7 days.

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Top Abstract 1 Introduction 2 Disorders associated with... 3 Treatment strategies:... 4 AVP receptor subtypes 5 AVP receptor antagonists 6 AVP V2 antagonists:... 7 AVP V2 antagonists:... 8 Vascular effects of... 9 AVP V2 antagonists:... 10 AVP V2 antagonists:... 11 Conclusions and future... References

 

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