We searched Medline, Google Scholar, and PubMed databases (1990–2007) for English language papers with the search term “vasopressin receptor antagonists”. We preferentially selected publications from the past 5 years, but did not exclude older publications that were commonly referenced or highly regarded. We searched the reference lists of articles identified by this search strategy and selected those we judged most relevant.
New Drug ClassNon-peptide arginine-vasopressin antagonists: the vaptans
Introduction
The vaptans are non-peptide arginine-vasopressin-receptor antagonists, that are orally and intravenously active (figure 1).1 A few vaptans have undergone sufficient clinical development to be on the market—eg, conivaptan in the USA and mozavaptan in Japan.
Arginine-vasopressin regulates osmolality by controlling urinary volume and composition. This hormone is synthesised by neurosecretory cells located predominantly in two specific hypothalamic nuclei—the supraoptic nucleus and the paraventricular nucleus. These neurons have axons that terminate in the neural lobe of the posterior pituitary gland (neurohypophysis) in which they release arginine-vasopressin (and oxytocin). Arginine-vasopressin is secreted in response to increases in plasma tonicity (very sensitive stimulus) or to decreases in plasma volume (less sensitive stimulus).2 The existence of a central vasopressinergic system is now well recognised—arginine-vasopressin acts as a neurotransmitter regulating many functions.3
The three receptor subtypes V1a, V1b, and V2 all belong to the large rhodopsin-like class-A G-protein-coupled receptor family. Their structures can be modelled on that of bovine rhodopsin. Table 1 shows the effects of the arginine-vasopressin-receptor subtypes in relation to their sites of expression.1, 2, 3, 4 V1 receptors exert their effects via activation of the phosphatidylinositol and 1,2,-diacylglycerol signalling pathways, whereas the V2 receptor activates the adenylylcyclase signalling pathway through the stimulatory G protein. The V1a receptors are widely distributed, mainly on vascular smooth muscle (table 1).1, 2, 3 Stimulation of these receptors is associated with vasoconstriction and cardiac hypertrophy, together with a range of other effects (table 1). The V1b receptors have little selective distribution1, 2, 3, 4 and their activation is part of the adaptive reaction to stress, leading to stimulation of adrenocorticotrophic hormone (ACTH) and endorphin release (table 1). The V2 receptor is expressed predominantly in principal cells of the renal-collecting-duct system, in which its activation leads to increased resorption of free water. Stimulation of V1a receptors occurs at plasma concentrations of arginine-vasopressin greater than those needed for the V2-dependent antidiuretic effects.
Section snippets
Mechanisms of action
All three subtypes of receptors are activated by the interaction of arginine-vasopressin mainly with the conserved residues lining a binding pocket located between the transmembrane alpha helices. Despite their distinct physiological roles, all three receptor subtypes have high sequence similarity and interact in a similar way with their sole natural agonist vasopressin; however, the interaction with specific antagonists relies on subtype-specific residues within the binding pocket of the
Therapeutic uses and trials
Relcovaptan (SR-49059) is a potent smooth muscle V1a-receptor antagonist in animals and man18 that has been tested in several phase II clinical trials. It has shown some effectiveness in patients with Raynaud's disease,19 dysmenorrhoea,20, 21 and preterm labour.22 Up to now, no convincing results are available with V1a-receptor antagonists in patients with hypertension. OPC-21268 exerts a weak antagonist effect in patients and on receptors and was developed before relcovaptan.23 It reduces
Future developments
At present, the only accepted indication for vasopressin-receptor antagonists is for the treatment of euvolaemic and hypervolaemic hyponatraemia. Most patients with hyponatraemia and serum sodium concentrations greater than 120 mmol/L are usually regarded as asymptomatic when the disorder develops slowly during many days.55, 56 We know that the presence of hyponatraemia is generally associated with an increase in morbidity and mortality,57, 58, 59 but this increase is usually thought to be due
Search strategy and selection criteria
References (79)
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Identification of the binding sites of the SR49059 nonpeptide antagonist into the V1a vasopressin receptor using sulfydryl-reactive ligands and cysteine mutants as chemical sensors
J Biol Chem
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Vaptans and the treatment of water-retaining disorders
Semin Nephrol
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Vasopressin receptor antagonists
Kidney Intern
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Multicenter, randomized, double-blind, placebo-controlled study on the effect of oral Tolvaptan on left ventricular dilation and function in patient with heart failure and systolic dysfunction
J Am Coll Cardiol
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Aquaretic effect of Lixivaptan, an oral, non-peptide, selective V2-receptor vasopressin antagonist, in New York Heart Association functional class II and III chronic heart failure patients
J Am Coll Cardiol
(2006) - et al.
A vasopressin receptor antagonist (VPA-985) improves serum sodium concentration in patients with hyponatremia. A multi-center, randomized, placebo-controlled trial
Hepatology
(2003) - et al.
The VPA study group: therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist: a randomized double-blind multicenter trials
Gastroenterology
(2003) Vasopressin antagonist in polycystic kidney disease
Kidney Intern
(2005)Long-term treatment of patients with inappropriate secretion of antidiuretic hormone by the vasopressin receptor antagonist conivaptan, urea or furosemide
Am J Med
(2001)