Sustained aquaretic effect of the V 2 ‐AVP receptor antagonist, RWJ‐351647, in cirrhotic rats with ascites and water retention

A disturbance in body water homeostasis is a common feature in advanced cirrhosis. This disturbance is always associated with the existence of ascites and is characterized by an inability to adjust the amount of water excreted in the urine to the amount of water ingested. Vasopressin (AVP) is of major importance in the pathogenesis of water retention and hyponatremia in cirrhosis. The current study assessed the renal, hormonal and hemodynamic effects induced by 10‐day chronic oral administration of RWJ‐351647 (0.5 mg kg −1 daily), a new nonpeptide V 2 ‐AVP antagonist, in rats with CCl 4 ‐induced cirrhosis, ascites and severe water retention. Urine volume (UV), urine osmolality and sodium and potassium excretion were measured daily. At the end of the study, systemic hemodynamic parameters were also assessed. Long‐term administration of RWJ‐351647 has an aquaretic effect in rats with cirrhosis, ascites, water retention and hypo‐osmolality. It increases UV (ANOVA: F =7.32, P <0.0001) and reduces urine osmolality (ANOVA: F =12.69, P <0.0001) throughout the entire period of treatment, thereby leading to a greater renal ability to excrete a water load at the end of the 10‐day treatment period (the percentage of water load excreted improved from 30±8 to 92±21%, P <0.025). The nonpeptide AVP V 2 ‐receptor antagonist RWJ‐351647 also increased sodium excretion without affecting creatinine clearance and blood pressure. These data suggest that RWJ‐351647 could be therapeutically useful in the treatment of water retention in human cirrhosis.British Journal of Pharmacology (2005) 146 , 654–661. doi: 10.1038/sj.bjp.0706375