Vasopressin (AVP) stimulates collecting duct water reabsorption through cAMP mediated membrane targeting and increased expression of the aquaporin 2 (AQP2) water channel. Rats with liver cirrhosis induced by common bile duct ligation (CBL) show decreased protein expression of AQP2 despite increased plasma concentrations of AVP. The present study was conducted to investigate possible mechanisms behind this uncoupling of AVP signaling. The rats were examined four weeks after CBL or Sham-operation. The CBL rats had increased plasma AVP concentrations (CBL: 3.2±0.2 vs. Sham: 1.4±0.4 pg/mL, p<0.05) and reduced AQP2 (0.62±0.11%) and phosphorylated AQP2 (0.50±0.06%) protein expression when compared to Sham. However, examination of subcellular AQP2 localization by immunohistochemistry showed unchanged plasma membrane targeting in CBL rats indicating a sustained ability of AQP2 shortterm regulation. In a separate series of animals thirsting was found to normalize AQP2 expression, indicating that AVP uncoupling in CBL rats is a physiological compensatory mechanism aimed at avoiding dilutional hyponatremia. Studies on microdissected collecting ducts from CBL rats showed decreased cAMP accumulation in response to AVP stimulation. The presence of the non-specific phosphodiesterase inhibitor IBMX normalized the cAMP accumulation, indicating that cAMP-phosphodiesterase activity is increased in CBL rats. However, in contrast to this Western blotting showed a decreased expression of several phosphodiesterase splice variants. We conclude that CBL rats develop an escape from AVP to prevent the formation of dilutional hyponatremia in response to increased plasma AVP concentrations. The mechanism behind AVPescape seems to involve decreased collecting duct sensitivity to AVP as a result of increased cAMP-phosphodiesterase activity.