Effect of the V1a/V2-AVP receptor antagonist, Conivaptan, on renal water metabolism and systemic hemodynamics in rats with cirrhosis and ascites.
BACKGROUND
Selective V(2)-AVP receptor antagonists are effective in inducing aquaresis in humans and rats with cirrhosis, hyponatremia and water retention. However, it is unknown whether dual V(1a)/V(2)-AVP antagonists are also efficacious as aquaretic agents under these conditions. This is important, particularly considering that blockade of V(1a)-AVP receptors could aggravate cardiocirculatory function in decompensated cirrhosis.


OBJECTIVE
To evaluate the renal, hormonal and hemodynamic effects induced by the chronic oral administration of the V(1a)/V(2)-AVP antagonist, Conivaptan, in rats with CCl(4)-induced cirrhosis, ascites and severe water retention.


METHODS
We assessed the aquaretic efficacy of 10-day chronic oral administration of Conivaptan (0.5mg/kg body weight (bw)) in cirrhotic rats with hyponatremia and water retention. Urine volume (UV), osmolality (UOsm), and sodium excretion (U(Na)V) were measured daily. At the end of the study arterial pressure was also measured.


RESULTS
Conivaptan produced an acute increase in UV, a reduction in UOsm and, at the end of the investigation, cirrhotic rats receiving the V(1a)/V(2)-AVP receptor antagonist did not show hyponatremia or hypoosmolality. Conivaptan also normalized U(Na)V without affecting creatinine clearance and arterial pressure.


CONCLUSIONS
Dual V(1a)/V(2)-receptor antagonists may be therapeutically useful for the treatment of water retention and dilutional hyponatremia in human cirrhosis.
Fernández-Varo
Guillermo
G
Hormonal Laboratory, Hospital Clínic Universitari, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona and Instituto Reina Sofia de Investigaciones Nefrológicas (IRSIN), Villarroel 170, 08036, Barcelona, Spain.
Ros
Josefa
J
Cejudo-Martín
Pilar
P
Cano
Carmen
C
Arroyo
Vicente
V
Rivera
Francisca
F
Rodés
Juan
J
Jiménez
Wladimiro
W
D000284:Administration, Oral; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001201:Ascites / Q000209:etiology*; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology*; D004231:Diuresis / Q000187:drug effects; D004334:Drug Administration Schedule; D006439:Hemodynamics / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000097:blood / Q000150:complications / Q000503:physiopathology*; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D009994:Osmolar Concentration; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000097:blood; D014556:Urine / Q000737:chemistry; D014867:Water / Q000378:metabolism*
D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D014867:Water; C106389:conivaptan; D012964:Sodium