Abstract

Water retention in experimental cirrhosis can be reversed by blocking V₂-vasopressin (AVP) receptors with the nonpeptide antagonist OPC-31260 or by using the κ-opioid receptor agonist niravoline, a compound inhibiting central AVP release. However, reluctance to use these drugs in human beings has emerged because the former loses aquaretic efficacy in rats after 2 days of treatment and the latter may have adverse effects in humans. Recently, a new potent and selective nonpeptide V₂-AVP receptor antagonist, SR121463, has been developed that could be useful for the treatment of dilutional hyponatremia in human cirrhosis. The current study assessed the aquaretic efficacy of 10-day chronic oral administration of SR121463 (0.5 mg/kg/day) in cirrhotic rats with ascites and impaired water excretion after a water load (minimum urinary osmolality >160 mOsm/kg and percentage of water load excreted <60%). Urine volume (UV), osmolality (U_OsmV), and sodium excretion (U_NaV) were measured daily. At the end of the 10-day treatment, mean arterial pressure also was measured. In basal conditions cirrhotic rats showed ascites, sodium retention, and impaired water excretion. UV, U_OsmV, and U_NaV did not change throughout the study in cirrhotic rats receiving the vehicle. In contrast, SR121463 increased UV and reduced U_OsmV during the 10-day treatment. This resulted in a greater renal ability to excrete a water load and normalization in serum sodium and osmolality. During the first 6 days of treatment, SR121463 also increased U_NaV without affecting mean arterial pressure. These data suggest that SR121463 could be of therapeutical value for chronic management of human cirrhosis.