1 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. 2 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. 3 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). 4 The nonpeptide AVP V(2)-receptor antagonist
RWJ-351647 also increased
sodium excretion without affecting
creatinine clearance and blood pressure. 5 These data suggest that
RWJ-351647 could be therapeutically useful in the treatment of water retention in human
cirrhosis.