Long-term aquaretic efficacy of a selective nonpeptide V-2-vasopressin receptor antagonist, SR121463, in cirrhotic rats

Water retention in experimental cirrhosis can be reversed by blocking V-2-v asopressin (AVP) receptors with the non-peptide antagonist OPC-31260 or by using the kappa-opioid receptor agonist niravoline, a compound inhibiting c entral AVP release. However, reluctance to use these drugs in human beings has emerged because the former loses aquaretic efficacy in rats after 2 day s of treatment and the latter may have adverse effects in humans. Recently, a new potent and selective non-peptide V-2-AVP receptor antagonist, SR1214 63, 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 l oad (minimum urinary osmolality >160 mOsm/kg and percentage of water load e xcreted <60%). Urine volume (UV), osmolality (UOsmV), and sodium excretion (UNaV) were measured daily. At the end of the 10-day treatment, mean arteri al pressure also was measured. In basal conditions cirrhotic rats showed as cites, sodium retention, and impaired water excretion. UV, UOsmV, and UNaV did not change throughout the study in cirrhotic rats receiving the vehicle . In contrast, SR121463 increased UV and reduced UOsmV during the 10-day tr eatment. This resulted in a greater renal ability to excrete a water load a nd normalization in serum sodium and osmolality. During the first 6 days of treatment, SR121463 also increased UNaV without affecting mean arterial pr essure. These data suggest that SR121463 could be of therapeutical value fo r chronic management of human cirrhosis.