V2-vasopressin receptor antagonists—mechanism of effect and clinical implications in hyponatraemia

Catrin Palm and Peter Gross

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

Correspondence and offprint requests to: Dr Catrin Palm, Division of Nephrology, Department of Medicine, Universitätsklinikum C. G. Carus, Fetscherstr. 74, D-01307 Dresden, FRG.

Keywords: cardiac failure; liver cirrhosis; syndrome of inappropriate antidiuretic hormone secretion; treatment of hyponatraemia; vasopressin; vasopressin receptor antagonists

Introduction

Hyponatraemia (serum sodium <135 mmol/l) is the most frequent electrolyte disturbance in clinical practice. Its clinical relevance is related to both the symptoms it causes and the state of cardiovascular dysfunction it indicates. Hyponatraemic patients may suffer from lethargy, difficulty of concentration, disorientation, muscular cramps, grand mal seizures, and even coma. It is important to know that these symptoms are more related to the rate of decrease of serum sodium concentration than to the absolute level of a hyponatraemia reached. This surprising observation is related to the phenomenon of osmotic unloading of cells, which causes adaptation of cell volume to any given degree of hyponatraemia within 2–4 days. Osmotic reloading will have to occur during correction of hyponatraemia. Since this will take a similar amount of time to be completed, the rate of correction of hyponatraemia should not be in excess of 0.5 mmol/l/h. If chronic hyponatraemia is corrected too fast, i.e. at a rate exceeding 0.5 mmol/l/h, and if it reaches hypernatraemic levels, the patient will be at risk of brain damage. In the literature, the occurrence of central pontine myelinolysis has been well documented in such circumstances.

Pathophysiological significance of hyponatraemia

Hyponatraemia is encountered in the advanced stages of congestive heart failure (CHF), liver cirrhosis, and volume contraction (`prerenal pattern') as well as in the syndrome of inappropriate antidiuretic hormone secretion (`SIADH-pattern', Table 1Go). Hyponatraemia is a disorder of vasopressin excess, caused by non-osmotic vasopressin release. Vasopressin increases water reabsorption by the kidney. When such patients drink higher than minimal amounts of water (more than approximately 800 ml per day) vasopressin excess will lead to water retention. Consequently, dilution of all fluid compartments sets in, including dilution of the intravascular compartment leading to hyponatraemia. When daily fluid intake is limited to approximately 800 cc, however, obligatory fluid losses via kidney, GI-tract, and lungs will match intake and the water balance will become negative. Physicians often approach hyponatraemia as if it was a primary disorder of sodium deficiency. A vast body of published observations documents that this is an erroneous interpretation. Hyponatraemia is almost always a condition of water excess. Therefore the above interpretation may lead to deleterious therapeutic measures.


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Table 1. Categories of hyponatraemia
 
The causes of the non-osmotic vasopressin release in hyponatraemia have been studied intensively. In pre-renal hyponatraemia it was found that baroreceptor activation in the large central arteries is the culprit. The low arterial blood pressure typically present in the advanced stages of heart failure, liver cirrhosis and volume contraction provides the stimulus to such baroreceptor activation. In SIADH-type hyponatraemia, the stimuli of non-osmotic vasopressin release are not precisely known. These may originate either from tumour cells or from the hypothalamus.

Significance of hydro-osmotic V2-vasopressin receptors

The effects of vasopressin (antidiuretic hormone) to cause water retention and hyponatraemia are related to its action on the kidney. The effects come about by activation of a specific receptor—the V2-vasopressin receptor—which is expressed on collecting duct cells and on cells of the thick ascending loop of Henle of the nephron. In the latter (as well as in a fraction of collecting duct cells) the activated V2 receptor increases sodium reabsorption. In this way vasopressin enhances medullary tonicity and hence the driving force for water reabsorption. In collecting duct principal cells, however, the stimulation of the V2 receptor by vasopressin increases water reabsorption directly. This is achieved by the insertion of `water channels' of the aquaporin-2 type into the apical cell membrane of otherwise water-impermeable collecting duct epithelial cells.

The V2-vasopressin receptor itself has been cloned and sequenced recently [1]. The receptor resembles other rhodopsin like proteins and has seven transmembrane domains. About 60 different mutations of the V2 receptor have been described so far, and they are all associated with nephrogenic diabetes insipidus, i.e. with increased free water excretion. The latter finding suggests that water-retaining disorders such as those associated with hyponatraemia may be amenable to therapies inactivating or antagonizing the renal V2 receptor. Indeed, a number of vasopressin antagonists have been generated to achieve these ends.

Pharmacology of vasopressin V2 receptor antagonists

There has been rapid progress in developing new effective oral V2- (and V1)—vasopressin antagonists over the last 5 years. The major pharmacological properties of the most intensively studied V2 antagonists are given in Table 2Go.


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Table 2. V2-vasopressin receptor antagonists
 
All three agents cited are currently in clinical testing. VPA-985 appears to be the leading agent, since a number of publications in abstract form indicate steady progress in its clinical characterization [25].

Studies of vasopressin V2 antagonists in cardiac failure

At this time, almost all reported studies of vasopressin V2 and V1 antagonists have been performed in animal models. An exception to the latter is the recent study by Abraham et al. [2] in humans.

Basically, all studies have documented beneficial effects of vasopressin antagonists on water excretion in cardiac failure. Xu et al. [6] studied a rat model of cardiac failure with ligation of coronary arteries. They demonstrated a defect in renal water excretion depending on the degree of cardiac failure. Treatment of water retention with the V2 antagonist OPC 31260 reversed this defect. As a consequence of the increase in water diuresis (also called aquaresis) there was a rise in plasma osmolality eventually reaching normal plasma osmolality, i.e. normonatraemia. Other studies in models of cardiac failure have confirmed these observations [79]. Of interest is the fact that one study also indicated an improvement of the overall survival in heart failure when the V2 antagonist was given on a chronic basis over several months [9]. The data suggest that V2 antagonists exert some of their beneficial effects by a reduction in extracellular fluid volume. This is shown by the observed decreases of plasma ANP, right ventricular systolic pressure, left ventricular end-diastolic pressure, and reduction in cardiac weight. It is also important to point out that a V1 vasopressin antagonist (OPC 21268) had no effect on cardiac weight or on haemodynamic parameters in cardiac-failure models [9]. The latter evidence may be taken to indicate that the increase of plasma vasopressin concentrations that must be expected during V2-antagonist treatment is unlikely to have untoward cardiac side-effects on account of unopposed and increased V1 activity. It has also been suggested on the basis of studies in dogs that the combination of V2 plus V1 antagonism offers specific benefit in cardiac failure [8].

An intriguing observation of the effects of V2 antagonism has been made by Okada et al. [10] in vascular smooth muscle cells in culture. They found an increase of intracellular ionized free calcium during the hypo-osmolality of hyponatraemia. This caused an enhanced response to vasoconstrictor agents [10]. In this situation a V2 antagonist reversed the previous changes. A mechanism of this kind might explain some of the beneficial effects of V2 antagonism in hyponatraemic cardiac failure—beyond what may be explained by effects of V2 antagonists on the extracellular fluid volume alone.

Recently, Abraham et al. [2] gave VPA-985 in a short-term study to 28 patients in advanced cardiac failure (NYHA II–III). They documented a significant decrease of the urinary osmolality and a reciprocal increase of the water diuresis in response to VPA-985. Two multicentre studies administering VPA-985 for up to 1 week are currently in progress in Europe and North-America. Preliminary results indicate that the findings of Abraham and Schrier are confirmed also during chronic administration [4]. In addition, preliminary observations in these studies indicate that VPA-985 may be of haemodynamic benefit to the volume-overloaded state of advanced cardiac failure [4].

Studies of vasopressin V2 antagonists in liver cirrhosis

Non-osmotic release of AVP has also been implicated in the abnormal water metabolism, water retention, and subsequent hyponatraemia in liver cirrhosis [1114]. Baroreceptor activation and stimulation of vasopressin release in cirrhotic patients results from arterial underfilling. The latter is related to peripheral vasodilatation, hypoalbuminaemia, and splanchnic venous pooling. Moderate to severe hyponatraemia is common in end-stage liver cirrhosis.

Tsuboi et al. [14] documented significantly elevated plasma levels of AVP in decompensated cirrhotic rats. An acute oral water load suppressed AVP to levels <1 pg/ml in control rats; however, this effect could not be shown in the cirrhotic rats. The latter continued to have elevated AVP despite the water load. Because the water load decreased plasma osmolality, this observation demonstrates the presence of non-osmotic stimuli for AVP secretion. The authors went on to show a significant increase (by about 200%) of the water load excreted when the V2 vasopressin antagonist OPC 31260 had been given in conjunction with the water load [14]. The mean arterial blood pressure and the GFR remained unaltered by OPC 31260.

Inoue et al. [15] reported the aquaretic response to a single dose of OPC 31260 in eight patients with biopsy-proven cirrhosis. The patients had ascites and/or peripheral oedema (Child-Pugh A and B). A single oral dose of 30 mg of OPC 31260 induced a hypotonic diuresis in which the urinary excretion rate increased (from 51.2±7.6 to 135.1±36.4 ml/h, P<0.01) in patients with cirrhosis. The authors noted, however, that this response was less than the one observed in healthy controls receiving the same dose of OPC 31260 (52.7±5.3 ml/h at baseline, 336.4±33.1 ml/h, 2 h after OPC administration)[15].

The assessment of the potential clinical usefulness of a sustained blockade of the V2 vasopressin receptors in patients with cirrhosis requires further investigation. Preliminary and promising results have been reported in abstract form [4]. It was noticed, however, that cirrhotic patients must be watched closely to prevent an overly rapid aquaresis with hypovolaemia and renal failure.

Bernat et al. [16] reported an inhibition of vasopressin-mediated release of haemostatic factors (factor VIII, von Willebrand factor, tissue-type plasminogen activator) after blockade of endothelial V2 receptors [16]. It remains to be clarified whether these V2 receptor effects are clinically relevant during sustained blockade of V2 vasopressin receptors.

Taken together the use of aquaretic V2 antagonists in hyponatraemic hydropic liver cirrhosis appears to be a useful therapeutic option.

Studies of V2 vasopressin antagonists in SIADH

In the syndrome of inappropriate antidiuretic hormone (SIADH) AVP plasma levels, which may be in the `normal' range, are inappropriately elevated for the degree of hypo-osmolality (hyponatraemia) [12,17]. But it clearly is still unresolved whether there are indeed rare cases of hyponatraemia similar to SIADH but caused by SIAD—syndrome of inappropriate diuresis—without detectable ADH, as claimed by Robertson et al. 15 years ago [18]. This possibility would be confirmed by the demonstration that the V2 antagonist has no effect on SIAD-related hyponatraemia.

The therapeutic efficacy of two different V2 vasopressin antagonists (including OPC 31260) has been demonstrated in a rat model of SIADH by Fujisawa et al. [19]. OPC 31260 led to a significant decrease of urinary osmolality with an associated increase of the plasma sodium concentration. In addition, Fujita et al. showed a reduction of AQP-2 mRNA and of aquaporin-protein in the kidney in SIADH after OPC 31260 [20].

Saito et al. were the first to report results of a clinical trial of V2 receptor antagonism using OPC 31260 in hyponatraemic SIADH in patients [21]. They demonstrated prompt and dose-dependent increases in the urinary volume and the free water excretion in these patients while urinary osmolality decreased as expected. The cardiovascular system and the urinary excretion of sodium and potassium all remained unaffected in their trial. The plasma sodium concentration increased rapidly to reach near normal levels in those studies. Promising results have also been reported in abstract form with VPA-985 in patients with SIADH [4]. Thus, V2 vasopressin antagonists offer a new approach to the treatment of hyponatraemia in SIADH.

Conclusions

The development of selective oral V2 vasopressin receptor antagonists has led to (i) confirmation of established concepts of the pathogenesis of clinical hyponatraemia, and (ii) attempts to treat hyponatraemia on the basis of such concepts. As far as one can say at this time, the V2 vasopressin antagonists appear to pass both tests.

However, a note of caution is also indicated. The possible side-effects include increases in AVP plasma concentration [8,22,23]. This might theoretically contribute to vasoconstriction by activation of V1 receptors. In addition, overly rapid aquaresis may turn out to be an unwanted effect, potentially predisposing to acute renal failure and even central pontine myelinolysis. The former may be of relevance in liver cirrhosis, a situation in which the kidney is highly vulnerable to haemodynamic alteration. On the other hand, in advanced cardiac failure aquaresis appears to be haemodynamically beneficial beyond just correcting hyponatraemia. Other aspects include the question whether chronic V2 antagonism may cause bleeding from interference with the haemostatic system. This question awaits clarification. Escape from the aquaretic effects of V2 vasopressin antagonists has not been documented.

Taken together, the available evidence indicates that the treatment of hyponatraemia is facilitated and improved by V2 antagonists. In addition, the management of plasma volume expansion may be facilitated by V2 vasopressin antagonists in advanced cardiac failure and liver cirrhosis.

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