Sustained aquaretic effect of the V₂‐AVP receptor antagonist, RWJ‐351647, in cirrhotic rats with ascites and water retention

Abstract

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 À1 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 ¼ 7.32, Po0.0001) and reduces urine osmolality (ANOVA: F ¼ 12.69, Po0.0001) 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 3078 to 92721%, Po0.025). 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.

A novel model of CCl4-induced cirrhosis with ascites in the mouse

“…We decided to employ CCl 4 as the hepatotoxin since the corresponding model in the rat has been demonstrated to closely reproduce the events leading to ascites formation in man, such as hyperdynamic circulatory syndrome [15], renal sodium retention from the preascitic stage [4], and impaired renal water metabolism [16]. Based on the rat model, we also associated phenobarbital administration in the drinking water to selectively enhance CCl 4 hepatotoxicity.…”

Pharmacology of vasopressin antagonists

“…No human studies with chronic administration are available yet. In rats with CCl 4 -induced experimental cirrhosis, 10-day treatment with RWJ-351647 showed preserved efficacy after repeated administrations [31]. Detailed prescribing information with pharmacokinetic data and contraindications is available [32].…”

Prevention of Fibrosis Progression in CCl4-Treated Rats: Role of the Hepatic Endocannabinoid and Apelin Systems

“…; Sigma-Aldrich Chemie GmbH, Taufkirchen, Germany) and prepared with a polyvinyl-50 catheter in the left femoral artery. The animals were prepared for measurements of hemodynamic parameters as described previously (Ros et al, 2005). Hemodynamic parameters were allowed to equilibrate for 30 min, and values of mean arterial pressure (MAP), portal pressure (PP), and heart rate were recorded.…”