RECEPTOR ANTAGONISTS Vasopressin V2 Receptor Antagonists

1 RECEPTOR ANTAGONISTS

Vasopressin V2 receptor antagonists

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

(Requests for offprints should be addressed toJGVerbalis; Email: [email protected])

Abstract

Hyponatremia, whether due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) or disorders of water retention such as congestive heart failure and cirrhosis, is a very common problem encountered in the care of medical patients. To date, available treatment modalities for disorders of excess arginine vasopressin (AVP) secretion or action have been limited and suboptimal. The recent discovery and development of nonpeptide AVP V2 receptor antagonists represents a promising new treatment option to directly antagonize the effects of elevated plasma AVP concentrations at the level of the renal collecting ducts. By decreasing the water permeability of renal collecting tubules, excretion of retained water is promoted, thereby normalizing or improving hypo-osmolar hyponatremia. In this review, SIADH and other water retaining disorders are brieﬂy discussed, after which the published preclinical and clinical studies of several nonpeptide AVP V2 receptor antagonists are summarized. The likely therapeutic indications and potential complications of these compounds are also described. Journal of Molecular Endocrinology (2002) 29, 1Ð9

Introduction heart failure (CHF) and cirrhosis with ascites. In these disorders, a relatively decreased intravascular Arginine vasopressin (AVP), the ‘antidiuretic volume and/or pressure leads to water retention as a hormone,’ is the major physiological regulator of result of both decreased distal delivery of glomerular renal free water excretion. Increased AVP secretion filtrate and secondarily elevated plasma AVP levels. causes an antidiuresis, with subsequent retention of For example, hyponatremic patients with advanced water by the kidney. Disorders of AVP secretion congestive heart failure often have inappropriately cause imbalances of body water. The most elevated plasma AVP levels, which fail to sup- prominent of these is the syndrome of inappropri- press completely even after acute water loading ate antidiuretic hormone secretion (SIADH). (Goldsmith et al. 1986). This occurs because low Patients with SIADH fail to suppress AVP secretion cardiac output causes an underfilling of the arterial even when the plasma osmolality falls below the vascular compartment, which unloads barorecep- normal osmotic threshold for stimulating AVP tors thereby activating the renin–angiotensin– secretion (Zerbe et al. 1980). Total body water aldosterone system, the sympathetic nervous system increases as a result of the impaired renal water and AVP secretion in an effort to increase vascular excretion, causing dilutional hypo-osmolality and resistance and enhance renal Na+ and water reten- hyponatremia (Verbalis 2001). The clinical criteria tion. Similar mechanisms occur in patients with required for a diagnosis of SIADH remain basically advanced cirrhosis and ascites with edema (Bichet the same as when the syndrome was first described et al. 1982); despite a generalized hypervolemic by Bartter and Schwartz in 1967. edematous state, there is avid renal Na+ and water Hypo-osmolar hyponatremia also occurs rela- retention in an attempt to maintain the effective tively frequently in advanced stages of congestive arterial blood volume (Schrier 1988).

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Treatment strategies: disorders of at the V2 receptors in the collecting ducts of the hormone excess kidney. These agents, therefore, have the potential to increase free water excretion during states of Because SIADH is a disorder of relative AVP AVP excess, regardless of the cause of the AVP excess, it is rational to attempt to apply therapeutic hypersecretion. strategies similar to those used for other endocrine disorders of hormone excess. These include: (1) decreasing the secretion of the hormone, (2) AVP receptor subtypes decreasing the effects of the hormone at its target tissues, and (3) compensating for the effects All AVP receptor subtypes belong to the seven produced by the excess hormone secretion. transmembrane domain, G-protein-coupled recep- Although several drugs have been described that tor superfamily. Three known receptor subtypes decrease AVP secretion in some cases (e.g. ethanol, mediate all of the known actions of AVP; they are diphenylhydantoin, opiates), responses are erratic classified according to the second messenger system and often unpredictable. The second approach to to which they are coupled (Thibonnier et al. 1998). treating hormone hypersecretion, namely antago- The V1a and V1b (also known as V3) receptors are nizing the end-organ effects of the hormone, has linked to the phosphoinositol signaling pathway met with limited success. Until recently, pharmaco- with intracellular calcium acting as the second logical intervention for SIADH has been restricted messenger. In contrast, the V2 receptors are linked to drugs with predominantly post-receptor effects. to the adenylate cyclase signaling pathway with The tetracycline derivative, demeclocycline, causes intracellular cAMP acting as the second messenger. a nephrogenic form of diabetes insipidus, decreas- The V1a receptor subtype is ubiquitous and is ing urine concentration even in the presence of present on vascular smooth muscle cells, hepato- high AVP levels (Dousa & Wilson 1974). However, cytes and platelets where it mediates vascular demeclocycline can cause nephrotoxicity, especially constriction, glycogenolysis and platelet aggrega- in patients with cirrhosis, although in most cases tion respectively. V1b,orV3, receptors are found this has been reversible. Other agents, such as predominantly in the anterior pituitary where they lithium carbonate, have similar post-receptor mediate adrenocorticotropin release. V2 receptors effects but are less desirable because of inconsistent are present predominantly in the kidney collecting results and significant side effects. Because of the tubules where they mediate free water reabsorp- multiple problems associated with these therapies, tion. In addition, there is now evidence indicating the most frequently employed strategy in SIADH the presence of extrarenal V2 receptors, such as has been to attempt to compensate for the effects of those involved in von Willebrand factor secretion excess AVP secretion by restricting free water (Bernat et al. 1997). Activation of the V2 receptor in intake. Reduction of fluid intake to levels less than renal collecting ducts by circulating AVP leads to insensible losses plus kidney free water excretion an increase in intracellular cAMP by stimulating induces a negative water balance, with subsequent adenylate cyclase activity through Gs protein. This, increases in plasma osmolality and serum [Na+]. in turn, regulates renal free water excretion by Although fluid restriction can effectively counteract shuttling aquaporin-2 (AQP2) water channels from the effect of excess AVP secretion, it does not intracellular vesicles into the apical plasma directly inhibit excess hormone secretion, nor its membrane of the renal collecting duct cells, actions in the kidney. Furthermore, for many thereby increasing water permeability of the patients, long-term fluid restriction can be uncom- membrane and producing an antidiuresis (Nielsen fortable, difficult to maintain, and relatively et al. 1999). ineffective. With the cloning and sequencing of the receptors to which AVP binds, agents that can more directly AVP receptor antagonists antagonize the effects of the hormone at its receptors have now been synthesized. By virtue of Manning and Sawyer first designed peptide these actions, AVP V2 receptor antagonists are antagonists of both the antidiuretic and the promising agents that can block the actions of AVP pressor responses to AVP in the 1970s. Starting

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Downloaded from Bioscientifica.com at 09/30/2021 01:36:59AM via free access Vasopressin V2 receptor antagonists á J G VERBALIS 3 by modifying the highly specific and potent showed a relative V2:V1 selectivity of over antidiuretic peptide desmopressin, a selective 7000-fold in rat and 100-fold in human tissues. peptide V2 receptor agonist, they successfully SR-121463 also potently antagonized AVP- synthesized many vasopressin analogs that effec- stimulated adenylyl cylase activity. VPA-985, tively antagonized the antidiuretic response of AVP another potent selective nonpeptide V2 receptor in vivo (Manning & Sawyer 1991). However, despite antagonist, similarly inhibited binding of AVP to demonstrating potent V2 receptor antagonism in native V2 receptors in membrane isolates from rat animals, many V2 receptor antagonists tested in and dog renal medulla (Chan et al. 1998). In 1997, humans have paradoxically exhibited weak V2 Tahara et al. characterized a nonpeptide combined receptor agonism rather than antagonizing the V1a and V2 receptor antagonist, YM-087. This ff ffi antidiuretic e ects of AVP. Subsequent studies agent demonstrated a high a nity for V1a ff have suggested that this marked species di erence receptors from rat liver and V2 receptors from rat may be related to differences in kidney prosta- kidney. It interacted reversibly and competitively glandin activity in humans as compared with other with both receptors, and potently blocked AVP- species (Kinter et al. 1991). In addition to these induced cAMP production in cultured renal critical species differences in the action of peptide epithelium cells (Tahara et al. 1997), as well as V2 antagonist compounds in the kidney, poor oral dose-dependently displacing AVP radioligand bioavailability and short biological half-life have binding at V2 receptors in rat kidney medullary also limited their development as clinically useful membranes (Risvanis et al. 1999). agents for the therapy of water-retaining disorders. Conditions of extracellular fluid expansion such In 1992, Yamamura et al. characterized the first as congestive heart failure and liver cirrhosis are nonpeptide V2 receptor antagonist, OPC-31260 associated with increased kidney expression of the (Yamamura et al. 1992), which was discovered via a AVP-stimulated water channel, AQP2. Conversely, series of structural conversions of OPC-21268, an a reduction in kidney AQP2 levels have been found AVP V1a receptor antagonist discovered previously in several acquired forms of nephrogenic diabetes via a functional screening strategy. Of most insipidus (Knepper et al. 1997). OPC-31260 caused importance, this and similar compounds have a rapid and significant reduction in AQP2 mRNA subsequently been found to be devoid of V2 expression in rat kidney, and also significantly receptor agonist effects in humans. Additional diminished the increased expression of AQP2 advantages of the nonpeptide antagonists are that mRNA in collecting ducts of both rats with they are generally orally bioavailable, as well as experimentally induced SIADH and those with having a longer half-life than most peptides. cirrhosis (Christensen et al. 1998). These studies, therefore, have confirmed that modulation of AQP2 transcription in the kidney is primarily AVP V2 receptor antagonists: regulated via AVP V2 receptor signaling pathways. preclinical studies Animal studies have also shown that nonpeptide AVP V2 receptor antagonists are clearly ‘aquaretic’ In vitro studies have documented that nonpeptide agents, i.e. agents that selectively increase free V2 receptor antagonists inhibit binding of AVP to water excretion without inducing a significant V2 receptors. OPC-31260 was shown to antagonize solute diuresis, in contradistinction to ‘saluretic’ the binding of AVP to V2 receptors in rat kidney agents, such as furosemide, which increase urinary plasma membranes (Yamamura et al. 1992). In NaCl excretion to a much greater extent. Yatsu 1996, Serradeil-Le Gal and colleagues character- et al. (1997) demonstrated that YM-087 increased ized another orally active, nonpeptide AVP V2 free water excretion without increasing urinary receptor antagonist, SR-121463 (Serradeil-Le Gal excretion of electrolytes in the normally hydrated et al. 1996). This compound demonstrated highly conscious dog. In comparing the nonpeptide ffi competitive and selective a nity for V2 receptors V2 receptor antagonist OPC-41061, which was in rat, bovine and human kidneys, and in binding derived from OPC-31260, with furosemide in experiments SR-121463 was found to inhibit conscious rats, OPC-41061 was found to exert a [3H]AVP labeling to rat, bovine and human kidney purely aquaretic effect whereas equivalent diuretic membranes. Radioligand displacement studies doses of furosemide also exerted a natriuretic effect; www.endocrinology.org Journal of Molecular Endocrinology (2002) 29, 1Ð9

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as a result, OPC-41061 dose-dependently elevated dose dependently induced a water diuresis without the serum [Na+] while furosemide tended to altering urinary Na+ or potassium excretion, or decrease it (Hirano et al. 2000). blood pressure. In comparing its effect to Numerous in vivo animal studies have demon- furosemide, the diuretic effect was almost equi- strated the aquaretic effect (i.e. the ability to potent to furosemide, but furosemide induced a produce a water diuresis) of nonpeptide AVP V2 natriuresis acutely whereas OPC-31260 only receptor antagonists. Nonpeptide antagonists have caused a slight increase in urinary Na+, similar to been shown to produce a dose-dependent aquaresis the results of previous animal studies. No in both dehydrated and normally hydrated animals. undesirable signs or symptoms or changes in Seven days of treatment with oral YM-087 achieved laboratory safety parameters were observed a dose-dependent aquaresis in rats without affecting (Ohnishi et al. 1993). In a subsequent study, the same blood pressure or causing tachyphylaxis (Tahara group administered a single dose of oral OPC- et al. 1997), and SR-121463 similarly induced an 31260 in six dose steps to 6 normal subjects and effective, dose-dependent aquaresis after intra- compared them with 12 placebo-controlled subjects. venous or oral administration in rats (Serradeil-Le A dose-dependent aquaresis was produced without Gal et al. 1996). In addition, nonpeptide AVP V2 altering either the blood pressure or the heart rate, receptor antagonists have been shown to markedly and there were no adverse effects except for the increase free water excretion in animals with expected mild to moderate thirst that was tolerated water-retaining states such as experimental SI- well by all subjects (Ohnishi et al. 1995). In 1999, ADH, cirrhosis and CHF. Studies in which SIADH Burnier et al. demonstrated that a single dose of was produced in rats with administration of the YM-087 induced aquaresis in six healthy subjects, AVP V2 receptor agonist, desmopressin, revealed and it was similarly well tolerated without that OPC-31260 promptly induced a marked significant adverse clinical or biochemical events, water diuresis, as evidenced by an increase in or changes in blood pressure or heart rate; all urinary volume, a fall in urinary osmolality and subjects except one again reported the develop- normalization of serum [Na+] (Fujisawa et al. 1993). ment of increased thirst (Burnier et al. 1999). In dogs with congestive heart failure produced by Because V2 receptor antagonists will likely be rapid ventricular pacing, OPC-31260 induced most advantageous in conditions of water retention marked water diuresis that resulted in significant due to inappropriately elevated plasma AVP levels, increases in serum [Na+] and plasma AVP levels, such as SIADH, it was of particular importance to but did not produce either hemodynamic improve- investigate the effects of these agents in hydropenic ment or decompensation (Naitoh et al. 1994). A normal subjects who had increased endogenous similar aquaretic effect was seen in a post-infarction AVP secretion and maximally concentrated urine. heart failure model in rats treated with the Shimizu and colleagues demonstrated that intra- antagonist for as long as six months (Burrell et al. venous OPC-31260 caused a dose-dependent 1998). Interestingly, in dogs with pacing-induced aquaresis in normal human subjects under condi- congestive heart failure, the combined V1a and V2 tions of water restriction. Even in this mildly AVP receptor antagonist, YM-087, not only volume contracted group of subjects, no significant increased free water clearance, but also increased changes in blood pressure or heart rate, or other cardiac output and decreased left ventricular adverse effects, were reported (Shimizu 1995). end-diastolic pressure and total peripheral vascular These and other clinical studies have, therefore, resistance (Yatsu et al. 1999). demonstrated the ability to safely induce free water excretion using nonpeptide AVP V2 receptor antagonists in both normally hydrated and mildly AVP V2 antagonists: clinical studies volume depleted human subjects. Several Phase II-type trials have also been Phase I-type trials have established the relative conducted in patients with water retaining dis- safety of many nonpeptide V2 receptor antagonists orders, and these have similarly confirmed the ffi in humans. In 1993, Ohnishi et al. administered e cacy of nonpeptide V2 receptor antagonists in intravenous OPC-31260 to normally hydrated human patients with disorders of water retention. normal volunteers and demonstrated that the agent In 1997, Saito et al. administered OPC-31260

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Downloaded from Bioscientifica.com at 09/30/2021 01:36:59AM via free access Vasopressin V2 receptor antagonists á J G VERBALIS 5 intravenously to 11 patients diagnosed as having AVP V2 antagonists: potential chronic SIADH. A single dose of this agent therapeutic indications increased urinary volume and free water clearance in a dose-dependent manner. As a result, the The most certain indication for the clinical use of ff aquaretic e ect caused a significant increase in vasopressin V2 receptor antagonists will be SIADH. serum [Na+] by approximately 3 mmol/l after four Although there are many different etiologies for hours without changes in urinary solute excretion SIADH, it seems likely that AVP V2 receptor (Saito et al. 1997). Besides efficacy in patients with antagonists will prove to be efficacious regardless of SIADH, the nonpeptide antagonists also appear to the underlying pathophysiology of the disease. produce effective aquaresis in patients with liver Patients with ectopic sources of inappropriate cirrhosis. A single oral dose of OPC-31260 vasopressin secretion, such as small cell lung cancer administered to 8 patients with biopsy-proven and other tumor-related SIADH, should benefit cirrhosis with ascites or peripheral edema caused from inhibiting the effects of vasopressin at the increased urine excretion with a lowered urinary renal V2 receptor. Successful treatment of such osmolality. However, these aquaretic responses cases will allow liberalization of fluid restriction, as were only approximately half the responses that well as decreasing the morbidity associated with the were observed with similar doses in healthy subjects development of hypo-osmolar hyponatremia. An- (Inoue et al. 1998). Finally, efficacy has also been other likely subset of patients with SIADH who demonstrated in patients with congestive heart should benefit from AVP V2 receptor antagonist failure. Oral VPA-985 administration in 21 patients therapy are those with central nervous system with chronic New York Heart Association (NYHA) (CNS) disorders causing pituitary hypersecretion of class II or class III heart failure significantly in- AVP. Since these patients are often at high risk for creased free water clearance and decreased urinary confusion, falls and seizure activity, raising serum + osmolality as compared with placebo. VPA-985 [Na ] with an AVP V2 receptor antagonist would also significantly decreased urinary AQP2 in a dose- clearly be advantageous. Drug-induced SIADH is dependent manner (Martin et al. 1999). A recent also a potential indication for V2 receptor Phase II randomized, double-blind placebo- antagonist therapy, since many patients are unable controlled multicenter trial of VPA-985 adminis- to simply discontinue medications such as selective tered for up to seven days in 112 patients (61 with serotonin reuptake inhibitors, carbamazepine or liver cirrhosis and ascites, 14 with CHF, and 31 with phenothiazines in order to reverse the drug- SIADH) resulted in significant increases in serum induced SIADH. With the addition of an AVP V2 [Na+] and decreases in urine osmolality; both receptor antagonist, many such patients may be plasma osmolality and free water clearance in- able to continue taking necessary medications creased as well (Gross & Palm 2000). These and despite side effects of stimulating the release of other studies have therefore shown the efficacy of AVP or a potentiation of the effect of AVP on the nonpeptide vasopressin V2 receptor antagonists to kidneys. reverse impaired free water excretion in patients Other likely indications for AVP V2 receptor with SIADH, cirrhosis and congestive heart failure. antagonists include edema-forming states with Currently, several of the antagonists discussed diminished effective arterial circulation and second- above are already in, or are beginning, larger Phase arily inappropriately elevated AVP levels, such as III efficacy and safety trials. However, in a advanced congestive heart failure and cirrhosis. disturbing trend, further clinical development of Patients with CHF often do not correct hypo- some of these agents for treating disorders of water osmolar hyponatremia with conventional diuretic retention has been halted, apparently because of therapy. However, reversing impaired free water marketing concerns regarding the potentially excretion with AVP V2 receptor antagonists could limited number of patients who would be normalize dilutional hyponatremia in congestive candidates for their use. It will indeed be heart failure patients. V2 receptor antagonists will unfortunate if such financial concerns keep agents likely prove to be superior to conventional diuretics that are safe and efficacious from being utilized for in this setting, since they can induce free water a group of patients for whom therapies are limited diuresis without an accompanying solute diuresis. ff and often ine ective. AVP V2 receptor antagonist therapy may also be www.endocrinology.org Journal of Molecular Endocrinology (2002) 29, 1Ð9

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suitable in patients with cirrhosis, intractable ascites AVP V2 antagonist caused a free water diuresis and peripheral edema, who are often ineffectively despite unmeasurable plasma AVP levels (Kamoi treated with aldosterone antagonists and beta- 1997). blockers. In both congestive heart failure and Finally, AVP V2 receptor antagonist therapy cirrhosis with ascites, these agents may therefore could be a valuable adjunct to other diuretic improve quality of life by allowing increased fluid agents, such as furosemide, in the treatment of intake, and decrease morbidity by preventing or edematous states. Obviously, a solute diuresis in the correcting hypo-osmolality. form of natriuresis is desirable in patients with In addition to the above likely indications for edema-forming disorders. However, in many cases AVP V2 antagonists, there are several possible a combination of aquaretic and diuretic therapies additional indications for the use of such agents. may prove superior to diuretics alone, by virtue of These include: (1) prompt correction of sympto- producing a greater free water diuresis, avoiding matic hyponatremia, (2) diagnosis of vasopressin- hyponatremia, and requiring lesser potassium mediated hyponatremia, and (3) combination replacement therapy as a result of lower total therapy with diuretic agents. Cases of acute diuretic requirements. hyponatremia (generally defined as c48 h in duration) are usually symptomatic if the hyponatremia is severe (i.e. c120 mmol/l). These AVP V2 antagonists: potential patients are at greatest risk from neurological complications complications from the hyponatremia itself and + should be corrected to higher levels of serum [Na ] The known potential complications of AVP V2 promptly (Fraser & Arieff 1997). Standard therapy receptor antagonist therapy include central pontine of such patients is currently administration of myelinolysis due to an overly rapid correction of graded amounts of hypertonic (3%) NaCl (Ayus hyponatremia and inappropriate use in hypo- ff & Arie 1999), but titrated doses of AVP V2 volemic hyponatremia. Too rapid a correction of receptor antagonists may prove effective at severe hyponatremia can produce pontine and inducing a prompt but limited free water extrapontine myelinolysis, a brain demyelinating diuresis to increase serum [Na+] and prevent disease that can cause substantial neurological neurological complications from hyponatremic morbidity and mortality (Sterns et al. 1994). encephalopathy. Demyelination can occur independently of the Although the majority of patients with SIADH method used to correct hyponatremia in both have measurably elevated plasma AVP levels, in experimental animals and clinical studies, and some cases the diagnosis of AVP-mediated patients corrected too rapidly with AVP receptor hyponatremia is unclear. These patients clearly antagonists will also be at increased risk for brain demonstrate excessive free water retention and demyelination. Although correction of serum [Na+] meet all of the classical criteria for a diagnosis of in patients with acute hyponatremia carries little, if SIADH, but plasma AVP levels do not appear to any, risk of demyelination, patients with more be inappropriately elevated, and in some cases are chronic hyponatremia (>48 h in duration) can actually unmeasurable (Zerbe et al. 1980). This may develop demyelination after rapid correction be due to the presence of another circulating because of greater degrees of brain volume antidiuretic substance, or to increased AVP V2 regulation through electrolyte and osmolyte losses receptor sensitivity to very low AVP levels. In these (Verbalis 1998). There is no indication to correct cases, AVP V2 receptor antagonists would be ideal these patients rapidly, regardless of the initial agents not only for diagnosis, but also for plasma Na+ concentration. The same guidelines for treatment. A positive response to treatment with an treatment of hyponatremia should be followed AVP V2 receptor antagonist would confirm when using these agents as for other correction activation of the V2 receptor as a cause of this therapies such as hypertonic saline administration. disorder, versus post-receptor effects (e.g. direct In all cases, the rate of correction should be effects on AQP2 water channel insertion into the determined by weighing the risks of hyponatremia apical membranes of collecting duct cells). One against those associated with rapid correction. This such case has recently been reported in which an generally can be estimated by the patient’s duration

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Downloaded from Bioscientifica.com at 09/30/2021 01:36:59AM via free access Vasopressin V2 receptor antagonists á J G VERBALIS 7 of hyponatremia and the presence or absence of Conclusions and future projections neurological symptoms (Verbalis 1998). Although acute, symptomatic hyponatremia must be cor- It appears likely that we are poised to begin a rected quickly, in most patients a reasonable new era in both the evaluation and the treatment approach is controlled and limited correction that of patients with euvolemic or hypervolemic stays within the parameters shown to be safe from hyponatremia. Nonpeptide AVP V2 receptor previous clinical studies. This will likely be antagonists are clearly efficacious in producing a achievable by using titrated doses of AVP V2 free water diuresis in humans. Short-term studies in antagonists with careful monitoring of the patients with SIADH and congestive heart failure serum [Na+] during the active phase of the suggest that such agents will allow normalization of correction. plasma osmolality with less required restriction of Finally, AVP V2 receptor antagonists should fluid intakes. The resultant therapy of patients with only be used in euvolemic or hypervolemic chronic hyponatremia will very likely be much hyponatremic states (i.e. SIADH, congestive heart simpler and more effective than at the present failure, cirrhosis with ascites). It should be obvious time. However, the safe use of AVP V2 receptor that the use of AVP V2 receptor antagonists in antagonists will require avoidance of their use in hypovolemic hyponatremia will aggravate under- hypovolemic patients and caution with regard to lying hypovolemia and can potentially lead to the rate of correction of the hyponatremia induced. complications of dehydration and hypotension due Appropriate dosing and monitoring should allow to the increased free water excretion induced by successful adherence to the same guidelines for these agents in the presence of hypovolemia. limited controlled correction that apply to other Special caution should be exercised in patients with correction methods, and single doses of such agents cirrhosis who are at increased risk for intravascular may prove to be the ideal method for achieving volume depletion and renal failure. A careful small rapid corrections of serum [Na+] that will assessment of the patients’ clinical volume status satisfactorily reverse hyponatremic encephalopathy will therefore be essential before initiating treat- without producing excessive corrections with their ment with an AVP V2 receptor antagonist. Any subsequent neurological complications. The num- history consistent with volume depletion (e.g. bers of patients potentially benefiting from such thiazide diuretic use) or any clinical manifestations agents is difficult to project at this time, but since of disorders associated with volume depletion (e.g. hyponatremia remains the most common electro- primary adrenal insufficiency) are contraindications lyte disorder of hospitalized patients, and is to the use of either an aquaretic or a diuretic agent. particularly prevalent in the elderly, it seems likely Similarly, a low urinary Na+ concentration (i.e. that these agents will represent an important <30 mmol/l) should alert clinicians to the likeli- addition to our therapeutic armamentarium for hood of underlying hypovolemia. These patients treating disorders of water retention once they are should be treated initially with isotonic saline to shown to be safe in ongoing long-term clinical expand blood and extracellular volume; only if studies. hypo-osmolar hyponatremia persists after correction to a euvolemic state can an AVP V2 receptor antagonist then be safely employed. References In using these agents clinically, investigators and clinicians must also be attentive to potential Ayus JC & Arieff AI 1999 Chronic hyponatremic encephalopathy in ff postmenopausal women: association of therapies with morbidity unknown complications such as CNS side e ects and mortality [see comments]. JAMA 281 2299–2304. from blood–brain barrier penetration of lipophilic Bartter FC & Schwartz WB 1967 The syndrome of inappropriate nonpeptide vasopressin V receptor antagonists, secretion of antidiuretic hormone. American Journal of Medicine 42 2 790–806. although to date these have not been reported. Bernat A, Hoffmann P, Dumas A, Serradeil-Le Gal C, Raufaste D

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receptor antagonist, in dogs. European Journal of Pharmacology 321 Zerbe R, StropesL&Robertson G 1980 Vasopressin function in the 225–230. syndrome of inappropriate antidiuresis. Annual Review of Medicine Yatsu T, Tomura Y, Tahara A, Wada K, Kusayama T, Tsukada J, 31 315–327. Tokioka T, Uchida W, Inagaki O, Iizumi Y, TanakaA&Honda K 1999 Cardiovascular and renal eﬀects of conivaptan hydrochloride (YM087), a vasopressin V1A and V2 receptor antagonist, in dogs with pacing-induced congestive heart failure. Received 13 February 2002 European Journal of Pharmacology 376 239–246. Accepted 26 April 2002

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