Cardiovascular Research

Cardiovascular Research 2001 51(3):403-408; doi:10.1016/S0008-6363(01)00288-7
© 2001 by European Society of Cardiology

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Copyright © 2000, European Society of Cardiology

The role of V2 vasopressin antagonists in hyponatremia

Catrin Palm, Doreen Reimann and Peter Gross^*

Department of Medicine, Division of Nephrology, Universitätsklinikum C.G. Carus, Dresden, Germany

^* Corresponding author. Nephrology, MK III, U.K.D., Fetscherstrasse 76, 01307 Dresden, Germany peter.gross{at}tu-dresden.de

Received 15 December 2000; accepted 5 March 2001

	Abstract

Top Abstract 1 Pathophysiology of... 2 V2 vasopressin receptor... 3 Hyponatremia and V2... 4 Hyponatremia and V2... 5 Hyponatremia and V2... 6 Concluding remarks References

 
Hyponatremia is a frequent electrolyte disorder. It is often found in congestive cardiac failure, liver cirrhosis, plasma volume contraction and in SiADH. In these disorders hyponatremia is caused by nonosmotic vasopressin and sustained fluid intake. This provides a rationale for V2 vasopressin receptor antagonists in the treatment of hyponatremia. There is now convincing evidence from different animal models of congestive cardiac failure that peptide and non-peptide V2 vasopressin antagonists effectively increase renal water diuresis and plasma sodium concentration. In addition, several of the experimental studies also showed an improvement of hemodynamic changes of cardiac failure in response to V2 antagonists. Data in patients indicated that oral non-peptide V2-antagonists correct hyponatremia and may improve hemodynamic derangements in cardiac failure. In addition, experimental and clinical studies of V2 antagonists have been undertaken in liver cirrhosis and SiADH. In those studies hyponatremia was improved or corrected, too. Taken together, V2 vasopressin antagonists promise to become therapeutic agents in hyponatremic disorders.

KEYWORDS ANP, atrial natriuretic peptide; AQP, aquaporin water channel protein; CCF, congestive heart failure; CD, for collecting duct; GFR, glomerular filtration rate; MAP, mean arterial blood pressure; NDI, nephrogenic diabetes insipidus; PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure; SIADH, syndrome of inappropriate antidiuretic hormone; V2 R, vasopressin V2 receptor; VSMC, vascular smooth muscle cells

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Over the last nine years pharmaceutical research has uncovered novel agents that are effective oral vasopressin V2 receptor antagonists [1–6]. At this time most studies using the new agents have been conducted in experimental animals. Work in patients is just beginning. This overview is an attempt to outline the potential role of the new V2 vasopressin antagonists in the treatment of hyponatremia. The pathophysiology of hyponatremia has been described in the literature [7,8]. In the experience of the authors physicians sometimes are not fully aware of the pathophysiological concepts of hyponatremia. We will therefore begin by mentioning basic aspects of hyponatremia. This will establish the rationale for V2 vasopressin receptor antagonists in hyponatremia.

	1 Pathophysiology of hyponatremia

Top Abstract 1 Pathophysiology of... 2 V2 vasopressin receptor... 3 Hyponatremia and V2... 4 Hyponatremia and V2... 5 Hyponatremia and V2... 6 Concluding remarks References

 
Hyponatremic patients have hypoosmolality of their extra- and intracellular fluids, including blood plasma. Hyponatremia therefore is a disorder of the regulation of plasma osmolality. Under physiological circumstances fluid intake — controlled by thirst — and renal water excretion — regulated primarily by vasopressin — cooperate in such a way that plasma Na⁺ concentration (and effective plasma osmolality) are maintained within a narrow range of normal values (135–148 mmol/l; 280–300 mosM/kg).

Therefore in hyponatremia thirst and/or vasopressin will have to be dysregulated to bring about the hypoosmolality.

These questions have been studied. It was found that hyponatremia primarily occurred in a small number of underlying disturbances such as advanced cardiac failure [7–13], severe liver cirrhosis [9,11,14,15], plasma volume contraction [9,16] and SIADH [9,17,18]. When vasopressin was measured in such patients it was indeed stimulated — although it is normally suppressed at the lower limit of normal plasma osmolality. This stimulation has been called nonosmotic vasopressin secretion.

The stimuli of nonosmotic vasopressin release have also been studied [9–11,13–15,19–21]. It was observed that baroreceptor signals from the large central arteries stimulated vasopressin in the hyponatremia of advanced CCF and liver cirrhosis. In contrast in normal controls baroreceptors were without effect on vasopressin secretion [11]. This suggested that the nonosmotic vasopressin secretion could be accounted for by the low mean arterial blood pressure in those diseases. The same applies to hyponatremia in volume contracted states. On the other hand the stimuli of nonosmotic vasopressin secretion in SIADH are not precisely known.

Nonosmotic vasopressin alone is not sufficient to produce hyponatremia. For instance if fluid intake is lowered to an amount that will match daily involuntary losses (approx. 800 cc in an afebrile human) water balance, plasma osmolality and serum Na⁺ concentration will remain unaltered. Animal models of elevated serum vasopressin required a simultaneous increase of fluid input in order to produce hyponatremia [22]. Indeed it was shown in hyponatremic patients that they too have an elevated daily fluid intake which was found to be in the order of 2.0–2.5 l [9]. In other words, hyponatremic patients have ‘nonosmotic thirst’ in addition to nonosmotic vasopressin.

In clinical practice there can be several reasons for treating hyponatremia. For instance, the patient may have disturbing symptoms of hyponatremia. Or physicians having to give hyperalimentation to an already hyponatremic patient may be worried by the possibility of worsening the electrolyte disorder. It follows from the foregoing description that physicians have two options in treating hyponatremia: (a) they can try to limit fluid intake, (b) they can reduce vasopressin or its effect in the kidney. Fluid restriction is the present mainstay of treatment. However it is impractical, inefficient and difficult for the physician and the patient alike. Reducing the effect of vasopressin in a hyponatremic patient (without a risk of toxic side effects) has not been possible in the past. This appears to be changing. It is expected that the new V2 vasopressin receptor antagonists will provide a means for the treatment of hyponatremia that is nontoxic, specific and well-directed.

	2 V2 vasopressin receptor antagonists

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Historically, lithium carbonate — an agent for the prophylaxis of manic depressive disorder — and demeclocycline hydrochloride — a previously used tetracycline — were considered in the 1970s as a mode of therapy for hyponatremia [23–25]. This was based on their known side effects of partial nephrogenic diabetes insipidus. However, both agents were toxic in human hyponatremia and are no longer recommended.

Sawyer and co-workers described a large number of congeners of arginine vasopressin between 1970 and 1980 [26,27]. These agents showed competitive binding to the hydroosmotic V2 vasopressin receptor. However, some of the agents had partial agonistic properties, too, and potency was low [13,26–28]. Furthermore the compounds had to be given parenterally. This made their application impractical. They were never developed for clinical use in patients.

In 1992 Yamamura et al. described a nonpeptide orally active V2 vasopressin receptor antagonist (OPC-31260) for the first time [1]. Since then several other nonpeptide V2 or V1/V2 vasopressin antagonists have been characterized [2–6,29].

Reported pharmacological properties of currently studied V2 and V1/V2 receptor antagonists are given in Table 1. All agents cited are presently in various stages of development, including clinical trials. In these studies no major differences between individual agents in terms of their renal effects have emerged. We will therefore discuss them collectively as ‘V2 vasopressin receptor antagonists’.

View this table: [in this window] [in a new window]   Table 1 Non-peptide oral vasopressin receptor antagonists in clinical development

 

	3 Hyponatremia and V2 vasopressin receptor antagonists in cardiac failure

Top Abstract 1 Pathophysiology of... 2 V2 vasopressin receptor... 3 Hyponatremia and V2... 4 Hyponatremia and V2... 5 Hyponatremia and V2... 6 Concluding remarks References

 
3.1 Observations in experimental models
Vasopressin antagonists have been utilized in experimental models of CCF. In principle, Ishikawa et al. were the first to report an increased free water clearance in response to a V2 vasopressin receptor antagonist in a rat model of low output CCF [13]. Their publication appeared in 1986. They had used a peptide V2 receptor antagonist. Since then a number of additional studies have been performed, utilizing nonpeptide V2 receptor antagonists in animal models of CCF. Naitho et al. studied a CCF model in dogs induced by several days of rapid ventricular pacing (11–21 days). In this model, OPC 31260 induced a water diuresis (‘aquaresis’), associated with an increase of the serum Na⁺ concentration. There were no measurable hemodynamic changes in response to OPC 31260. The authors then combined OPC 21268 — a selective vasopressin V1 receptor antagonist with OPC 31260. In addition to the previously observed effects on water balance they now observed a decreased peripheral vascular resistance and a major increase of cardiac output. This was considered a beneficial hemodynamic response [12]. A study by Nishikimi et al. indicated an improvement of the overall survival in rats with CCF when these animals received treatment with a V2R antagonist [30]. In their model an aortocaval fistula was used to generate a high cardiac output form of CCF. OPC 31260 was given for 4 weeks. OPC 31260 caused decreases in plasma ANP, right ventricular systolic pressure, left ventricular end-diastolic pressure and cardiac weight. Surprisingly when the model of Nishikimi et al. was given OPC 21268, an oral V1 receptor antagonist, no changes were seen, i.e., there were no effects on hemodynamics, organ weight or concentrations of relevant hormones.

Therefore in animal models of CCF V2 antagonism and correction of hyponatremia was beneficial in terms of cardiovascular derangements. The reason(s) for this is (are) not clear. Conceivably V2 antagonism could have reduced intravascular fluid volume diminishing cardiac preload. In addition, hyponatremia itself — which is correctable by V2 antagonism — may be disadvantageous in CCF. For instance, Okada et al. demonstrated in cultured vascular smooth muscle cells (VSMC) that hyponatremia per se caused a decrease in Na⁺/Ca²⁺ exchange resulting in an increase of intracellular free ionized calcium [31]. The observed changes were reversible by correction of hyponatremia. Hypothetically an increased intracellular free ionized calcium availability in VSMC may have a role to increase peripheral vascular resistance. Furthermore Lang et al. described multiple changes of intracellular enzymes in hyponatremic cell swelling [32]. Such alterations may contribute to the metabolic malfunction of cardiomyocytes in CCF.

Taken together we may have to reconsider the role of hyponatremia in CCF. In the past hyponatremia was interpreted as a mere epiphenomenon of CCF. However the information described here suggests that hyponatremia may also contribute to CCF. This possibility is likely to make the V2 antagonists interesting agents in clinical hyponatremic CCF.

3.2 Observations in patients
Studies in patients with CCF using V2 antagonists are just beginning. Martin et al. reported urinary AQP-2 excretion in 21 patients with CCF (NYHA II–III, serum Na⁺ concentration ranging from 120 to 140 mmol/l) before and after administration of V2 receptor antagonist (WAY-VPA 985) [33]. In these studies the urinary AQP-2 excretion rate was taken as an indicator of renal collecting duct stimulation by vasopressin — as has been shown. Martin et al. found a dramatic decrease in urinary AQP-2 excretion rate. This occurred in a dose-dependent manner. The observations of AQP-2, together with the associated water diuresis in the patients lead the authors to conclude that WAY-VPA 985 was an efficient V2 receptor antagonist in CCF patients.

Similar results were also obtained in a study by Abraham et al. They used WAY-VPA 985 successfully in a placebo-controlled single-dose study in patients with CCF (NYHA II–III) [34]. We participated in a recent phase II, randomized, double-blind, placebo-controlled multicenter trial of WAY-VPA 985 in hyponatremic (<132 mmol/l) hospital in-patients. WAY-VPA 985 was given orally for up to 7 days at dosages of 50 or 100 mg b.i.d.

All 14 patients with congestive heart failure (NYHA II–III) were on a restricted fluid intake of 1200 ml/day. In contrast to placebo treatment, the V2 receptor antagonist significantly increased the serum Na⁺ concentration. Patients receiving the high-dose WAY-VPA 985 normalized their serum Na⁺ concentration. This was associated with a decrease of the urinary osmolality by approximately 50%. There was no evidence of tachyphylaxis during the 7-day period of the study. There were no cases of hypernatremia. There were no significant side effects of the medication. Thus, in these clinical studies a V2 receptor antagonist proved to be an effective and safe treatment of hyponatremia.

More recently Abraham et al. reported effects of the nonspecific V1A/V2 vasopressin receptor antagonist conivaptan (YM 087). They performed an open label study (study period 8 days) in six patients with hyponatremia (average serum Na⁺ concentration 126.2 mmol/l) in the setting of severe heart failure (NYHA III and IV). Conivaptan was started at a dose of 10 mg b.i.d. (orally). It was increased progressively (to doses of 20, 40, 60 mg b.i.d.) until a normalisation of the serum Na⁺ concentration or signs of intolerance occurred. Fluid intake was restricted to 1.5 l/day. Conivaptan was shown to increase the serum Na⁺ concentration significantly and safely in these patients [35]. The aquaretic effect of conivaptan has been confirmed in further studies using i.v. conivaptan [36,37]. It was noted in these studies that conivaptan did not have an effect on thirst [35,36]. The hemodynamic effect of i.v. conivaptan in patients (n=142) with congestive heart failure (NYHA III/IV) has been investigated in a placebo-controlled study by Udelson et al. [38]. They showed a significantly decreased PCWP and RAP after a single dose of conivaptan. There was no effect on systemic blood pressure or heart rate.

With regard to heart failure a note of caution is indicated. In studies using specific V2R antagonists increases of the plasma vasopressin concentration have been observed [30,39,40]. For instance in one study the plasma vasopressin concentration tripled in response to WAY-VPA 985 [41]. This has lead to concern about the possibility of an unopposed stimulation of the V1 receptor in such patients. Conceivably this could be counterproductive in CCF. Therefore a nonspecific V1A/V2 receptor antagonist might have advantages over a specific V2 receptor antagonist in the setting of CCF.

	4 Hyponatremia and V2 vasopressin receptor antagonists in liver cirrhosis

Top Abstract 1 Pathophysiology of... 2 V2 vasopressin receptor... 3 Hyponatremia and V2... 4 Hyponatremia and V2... 5 Hyponatremia and V2... 6 Concluding remarks References

 
4.1 Observations in animal models
In terms of vasopressin receptor antagonists, Tsuboi et al. published data on the V2 vasopressin receptor antagonist OPC-31260 in rats with CCl₄-induced cirrhosis and ascites. They first observed elevated plasma levels of vasopressin in their model. An acute oral water load, which is a standard test of vasopressin function in cirrhosis, suppressed vasopressin to levels <1 pg/ml in control but not in cirrhotic rats; the latter continued to have elevated plasma levels of vasopressin despite the water load. The water load test (30 ml/kg) showed the following results: the control rats excreted 102.1% of the water load in 3 h, while the cirrhotic rats excreted only 62.5%; however, when the cirrhotic rats received pretreatment by the V2 receptor antagonist OPC 31260 they excreted 215.1%, i.e.,150% more [42]. The treatment of cirrhotic rats with the V2R antagonist also resulted in an increased serum Na⁺ concentration, an increased plasma osmolality, but no changes of the GFR or the MAP in that study. These results therefore demonstrate the efficiency of V2R antagonism to induce aquaresis in experimental cirrhosis.

4.2 Observations in patients
Observations using vasopressin receptor antagonists in patients have now been reported in several studies. In a study by Inoue et al., eight patients with biopsy-proven cirrhosis (Child Pugh A and B) received the V2R antagonist OPC 31260 (30 mg) acutely [43]. The V2R antagonist induced a significant hypotonic diuresis (from 51.2±7.6 to 135.1±36.4 ml/h (P<0.01). Interestingly, the authors gave the same dose of V2R antagonist to healthy controls. It was observed that the aquaretic response in the normal controls was even larger than that in the cirrhotic patients. These results are not surprising. It is known that additional factors-such as GFR, increased proximal and distal tubular reabsorption — modify the renal water excretion and its control by vasopressin. Such additional factors are relevant to the kidney in cirrhosis. The largest study in cirrhotic patients is from Gerbes et al. [44]. They reported 60 patients with liver cirrhosis and hyponatremia (128±2 mmol/l). They performed a double-blind placebo-controlled prospective randomized study, in which they gave the V2R antagonist WAY-VPA 985 over up to 6 days. The end point of the study was correction of hyponatremia. All patients were on a fluid restriction (<1.2 l/day) throughout. The following was observed: (a) WAY-VPA 985 corrected the hyponatremia in most though not all patients; (b) SIADH with hyponatremia responded better to WAY-VPA 985 than cirrhosis; (c) there was no tachyphylaxis; (d) ‘side effects’ and adverse events occurred in the treated and the untreated hyponatremic patients with an equal frequency; and (e) hypernatremia did not occur.

These results are in agreement with the observations of Inoue et al. [43]. Another study of hyponatremia (<130 mmol/l), using the V1A/V2 receptor antagonist conivaptan (YM 087), in which our group participates, is currently in progress.

With respect to cirrhosis we would also like point out the following. First, it has been known for a long time that the kidney is susceptible to hepato-renal syndrome in liver cirrhosis, especially when there are reductions of plasma volume. Therefore it will be prudent to watch renal function closely during V2 vasopressin receptor antagonism. Secondly blood coagulation has not been evaluated during V2 vasopressin receptor antagonism so far. It is however well known that V2 agonists such as DDAVP stimulate factors VIII, vWF and tissue type plasminogen activator [45]. Indeed, one study using a selective V2 vasopressin receptor antagonist demonstrated an inhibition of vasopressin-mediated release of hemostatic factors [46]. The clinical role of such changes in patients with esophageal varices is presently unknown. None the less we conclude from the available literature that orally active V2 vasopressin receptor antagonists will provide effective new tools in the treatment of patients with hyponatremic liver cirrhosis.

	5 Hyponatremia and V2 vasopressin receptor antagonists in SIADH

Top Abstract 1 Pathophysiology of... 2 V2 vasopressin receptor... 3 Hyponatremia and V2... 4 Hyponatremia and V2... 5 Hyponatremia and V2... 6 Concluding remarks References

 
Fujisawa et al. reported studies in a rat model of SIADH. They demonstrated the therapeutic efficacy of the V2R antagonist OPC 31260. It reversed water retention in SIADH rats. The administration of OPC 31260 was associated with a significant decrease of urinary osmolality and an increase of the plasma Na⁺ concentration. In addition, OPC 31260 reduced the enhanced AQP-2 mRNA and protein expression in the kidney of rats with SIADH [17].

A clinical trial of V2 vasopressin receptor antagonism using OPC-31260 in hyponatremic SIADH patients has been undertaken [18]; Saito et al. demonstrated a prompt increase in urinary volume and free water excretion in response to OPC-31260. These changes occurred in a dose-dependent manner. Simultaneously the serum Na⁺ concentration increased, reaching near normal levels in these patients. The urinary excretion of Na⁺ and K⁺ remained unaffected. These kinds of observations have been confirmed. A structurally different selective V2 receptor antagonist (WAY-VPA 985) as well as a new combined vasopressin V1A/V2 receptor antagonist (YM 087) have been used successfully to treat SIADH in patients [41,44,36]. Decaux et al. studied the effect of WAY VPA 985 on different solute clearances in hyponatremic SIADH. They observed, that correction of hyponatremia was associated with a decrease in the fractional excretion of Na⁺, urea and uric acid in patients with SIADH but not in patients with cirrhosis [47]. It was demonstrated that V2R antagonism (WAY-VPA 985) was more effective in the hyponatremia of SIADH than in that of cirrhosis. Consequently, patients with SIADH receiving vasopressin antagonists may have to be watched closely to prevent an overly rapid correction of a chronic hyponatremia.

Taken together V2 vasopressin receptor antagonists appear to be useful for the treatment of water retention and hyponatremia in SIADH.

	6 Concluding remarks

Top Abstract 1 Pathophysiology of... 2 V2 vasopressin receptor... 3 Hyponatremia and V2... 4 Hyponatremia and V2... 5 Hyponatremia and V2... 6 Concluding remarks References

 
Observations of the regulation of vasopressin and its effect on collecting duct vasopressin receptors have provided a basis for the development of V2 vasopressin receptor antagonists. They are efficient aquaretic agents. ‘Aquaresis’ indicates a selective enhancement of renal water excretion by drugs. Presently these agents have shown promising results in the treatment of experimental and clinical hyponatremia.

In the future those agents may also prove useful in other ways. For instance V1 and V2 receptor antagonists will enable researchers to determine whether hyponatremia is associated with reductions of cerebral perfusion and which component — vasopressin or water retention — is the probable cause of the change. Similarly it will become possible to determine if hyponatremia and/or vasopressin contribute to peripheral vascular resistance in patients. It will also be learned how much is contributed by water itself to cardiac preload in hyponatremic cardiac failure. Therefore the new oral vasopressin antagonists will continue to attract the attention of researchers for some time to come.

Time for primary review 26 days.

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