Aquaretic-induced apoptosis : a cure or a curse?

Sir, Modern pharmacology is discovering selective vasopressin receptor-2 antagonists (the so called ‘aquaretic agents’) as one of the most promising drug classes for the treatment of refractory hyponatremia associated with disorders like heart failure and cirrhosis. However, recent findings regarding the biological involvement of V2 receptors (V2-R) have opened new interesting horizons in the therapeutic use of these molecules such as, for example, the treatment of Autosomal Polycystic Kidney Disease (ADPKD), a hereditary condition causing progressive renal failure for which as yet no specific cure is available [1]. In this case, by blocking a specific V2-R mediated intracellular pathway, aquaretic agents impressively reduce cellular growth and thus, cyst enlargement, slowing down the progression of disease [2]. This interesting effect suggests that V2-R antagonists may also directly influence cell biology and even proliferation. For this reason we aimed to assess the effect of increasing doses (0·25, 0·5, 1 and 2 μM) of the selective V2-R antagonist Satavaptan (Sanofi Research, Toulouse, France) on cell apoptosis in a culture model including the V2-R renal tubular line LLC-PK1 and the V2-R ovarian CHO line. As illustrated in Fig. 1, CHO cells did not manifest significant variations in apoptosis rate. On the contrary, the LLC-PK1 line showed significantly increased apoptosis percentages at all times and at every dose of Satavaptan added, compared to CHO cells. Furthermore, a significant trend in apoptosis rate was noticed among increasing doses of Satavaptan. As CHO cells seemed insensitive to Satavaptan-induced apoptosis, it could be presumed that this effect, observed on LLC-PK1 cells, may somehow be related to a specific interaction with V2-R. This consideration opens at least two points for discussion. First, as it has already been demonstrated that several types of tumour (such as breast, lung and pancreas) notably express normal and even anomalous forms of V2-R [3], it could be interesting to explore the possibility of another new therapeutic application of aquaretic agents as anti tumoural drugs as it has already been successfully reported for the treatment of ADPKD (a condition sharing several features with cancer) [4]. On the other hand, it is known that, physiologically, not only the renal tubule but also several other extra renal cells, such as the endothelium, express V2-R. As the use of V2-R antagonists is going to become