Therapeutic Potential of Vasopressin Receptor Antagonists
| Title: | Therapeutic Potential of Vasopressin Receptor Antagonists |
|---|---|
| Authors: | Ali, Farhan; Guglin, Maya; Vaitkevicius, Peter; Ghali, Jalal |
| Publisher: | Drugs |
| Date Published: | January 01, 2007 |
| Reference Number: | 723 |
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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This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)
In the pharmacological context, an antagonist is a substance that binds with a receptor in the body, thereby preventing what normally binds with the receptor from doing so. For example, the antidiuretic hormone, arginine vasopressin (AVP), binds to three different receptors: the vasopressin 2 receptor (V2R), the vasopressin 1A receptor (V1A), and the vasopressin 1B receptor (V1B). In each case, the binding of AVP to one of its receptors initiates a chemical cascade that provides a needed bodily process. For example, once AVP binds with V2R on the membrane of the principal cells of the kidney collecting duct, the chemical cascade that is initiated directs the aquaporin-2 protein (AQP2) into a section of the collecting duct principal cells called the apical cell membrane. When AQP2 is inserted into the apical membrane, water can flow through the collecting cells into the kidney interior, then into the blood. This is a major component of the body’s ability to maintain body water balance.
If a V2R antagonist were to bind with the V2R, then there would be no room for AVP to bind with the V2R, and the chemical cascade described above would not occur. However, there are situations where the presence of a vasopressin receptor antagonist may be therapeutic. In their paper, Ali, et al., review the potential therapeutic role of vasopressin receptor antagonists (VRAs). Though their paper reports on possible therapeutic benefits of the VRAs that affect all three types of vasopressin receptors, we shall focus on those that affect V2R due to their implications for Nephrogenic Diabetes Insipidus (NDI).
The vast majority of congenital NDI is due to mutations in the V2R gene that result in V2R proteins that are unable to perform their function. This means that AVP cannot bind to the mutant V2Rs and, as a result, the kidney can not affect body water balance. There are three types of V2R mutations. In type 1, the V2R mutants are unable to bind with AVP at the cell surface. In type 2, the V2R mutants are unable to travel from the cell’s quality control mechanism, the endoplasmic reticulum (ER), to the cell membrane surface. Type 3 mutations engender unstable messenger RNA transcription.
Patients whose NDI was due to type 2 mutations were given a type of VRA called relcovaptan. As a group, they experienced a significant increase in the concentration of their urine. (One symptom of NDI is copious amounts of dilute urine.) Since V2R mutants resulting from type 2 V2R mutations are unable to escape the ER, the results of the test indicate that relcovaptan may improve the ability of such V2R mutants to escape the ER and travel to the cell surface membrane. The authors view this finding as promising, but counsel that further study is needed.