Therapeutic Potential of Vasopressin Receptor Antagonists

Abstract

Arginine vasopressin (AVP) is a neuropeptide hormone that plays an important role in circulatory and sodium homeostasis, and regulating serum osmolality. Several clinical conditions have been associated with inappropriately elevated levels of AVP including heart failure, cirrhosis of the liver and the syndrome of inappropriate secretion of antidiuretic hormone. Three receptor subtypes that mediate the actions of AVP have been identified (V(1A), V(2) and V(1B)). Activation of V(1A) receptors located in vascular smooth muscle cells and the myocardium results in vasoconstriction and increased afterload and hypertrophy. The V(2) receptors located primarily in the collecting tubules mediate free water absorption. The V(1B) receptors are located in the anterior pituitary and mediate adrenocorticotropin hormone release. The cardiovascular and renal effects of AVP are mediated primarily by V(1A) and V(2) receptors. Antagonism of V(1A) receptors results in vasodilatation and antagonism of V(2) receptors resulting in aquaresis, an electrolyte-sparing water excretion. Several non-peptide AVP antagonists (vasopressin receptor antagonists [VRAs]) also termed 'vaptans' have been developed and are vigorously being studied primarily for treating conditions characterised by hyponatraemia and fluid overload. Conivaptan is a combined V(1A)/V(2)-receptor antagonist that induces diuresis as well as haemodynamic improvement. It has been shown in clinical trials to correct euvolaemic and hypervolaemic hyponatraemia, and has been approved by the US FDA for the treatment of euvolaemic hyponatraemia as an intravenous infusion. Tolvaptan, a selective V(2)-receptor antagonist, has undergone extensive clinical studies in the treatment of hyponatraemia and heart failure. It has been shown to effectively decrease fluid in volume overloaded patients with heart failure and to correct hyponatraemia. A large outcome study (n = 4133 patients) will define its role in the management of heart failure. Lixivaptan and satavaptan (SR-121463) are other selective V(2)-receptor antagonists being evaluated for the treatment of hyponatraemia. In addition, a potential role for the vaptans in attenuating polyuria in nephrogenic diabetes insipidus and cyst development in polycystic kidney disease is being explored. Ongoing clinical trials should further define the scope of the potential therapeutic role of VRAs.

Vasopressin V1a and V1b Receptors: From Molecules to Physiological Systems

“…These receptor antagonists are considered to be useful in clinical conditions associated with abnormal water retention or vasoconstriction mediated by inappropriately elevated levels of circulating AVP. Such high AVP levels are seen in patients with heart failure, SIADH, cirrhosis of the liver, polycystic kidney disease, nephrotic syndrome, surgical stress, and some forms of hypertension (18). Although peptide agonists and antagonists are considered to be difficult to formulate for oral consumption, desmopressin is now available in a tablet form for oral administration (18,294,323).…”

“…Such high AVP levels are seen in patients with heart failure, SIADH, cirrhosis of the liver, polycystic kidney disease, nephrotic syndrome, surgical stress, and some forms of hypertension (18). Although peptide agonists and antagonists are considered to be difficult to formulate for oral consumption, desmopressin is now available in a tablet form for oral administration (18,294,323). In addition to the peptide antagonists, several nonpeptide AVP receptor antagonists have been developed.…”

Arginine vasopressin (AVP) and treatment with arginine vasopressin receptor antagonists (vaptans) in congestive heart failure, liver cirrhosis and syndrome of inappropriate antidiuretic hormone secretion (SIADH)

“…The physiologic role of the V 3 R is not completely understood, it is presumed to be involved in corticotropin and glucagon release [10,11] in addition to cellular proliferation and differentiation effects [12].…”

Non-Peptide Arginine-Vasopressin Antagonists (Vaptans) for the Treatment of Hyponatremia in Neurocritical Care: A New Alternative?

“…Distinct from the currently available diuretics, which result in elimination of both free water and electrolytes (''natriuresis''), compounds acting at the V2 receptor cause elimination of free water only (''aquaresis''). By preserving plasma electrolytes but decreasing total body free water, aquaresis reliably increases plasma osmolality and the concentration of sodium, the major determinant of plasma osmolality [3,8]. Although vasopressin antagonists have been available since the 1960s, the original compounds were peptides which were limited by poor penetration into the central nervous system and more importantly, by a tendency to exhibit agonist effects when given chronically.…”

“…Developed in the 1990s, the nonpeptide AVP antagonists-also referred to as the vaptans-overcame these limitations [3]. This class of drugs now includes those that selectively antagonize the V1a receptor (reclovaptan, OPC-21268, SR-49059), the V1b receptor (SSR-149415), the V2 receptor (lixivaptan, satavaptan, and tolvaptan), and both the V1a/V2 receptor (conivaptan, mozavaptan) [3,6,8]. Thus far, only conivaptan has been approved for clinical use in the United States.…”