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Therapeutic Potential of Vasopressin Receptor Antagonists

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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 (V1A, V2 and V1b).

Activation of V1A receptors located in vascular smooth muscle cells and the myocardium results in vasoconstriction and increased afterload and hypertrophy. The V2 receptors located primarily in the collecting tubules mediate free water absorption. The V1B receptors are located in the anterior pituitary and mediate adrenocorticotropin hormone release.

The cardiovascular and renal effects of AVP are mediated primarily by V1A and V2 receptors. Antagonism of V1A receptors results in vasodilatation and antagonism of V2 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 V1A/V2-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 V2-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 V2-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.

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Acknowledgements

F. Ali, M. Guglin and P. Vaitkevicius have nothing to disclose. J.K. Ghali has received research grants from Astellas Pharma US, Inc., Deerfield (IL) and Otsuka Maryland Research Institute, Rockville (MD). We would like to thank Saiyeda S. Ali for her excellent technical assistance.

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  1. Heart Failure Program, Wayne State University, Detroit, Michigan, USA

    Farhan Ali, Maya Guglin, Peter Vaitkevicius &  Jalal K. Ghali

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  1. Farhan Ali
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Ali, F., Guglin, M., Vaitkevicius, P. et al. Therapeutic Potential of Vasopressin Receptor Antagonists. Drugs 67, 847–858 (2007). https://doi.org/10.2165/00003495-200767060-00002

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