THERAPEUTIC EFFICACY OF THE NONPEPTIDE AVP ANTAGONIST OPC-31260 IN CIRRHOTIC RATS

The present study was undertaken to determine whether a non-peptide ar ginine vasopressin (AVP) antagonist lamino)benzoyl}-2,3,4,5-tetrahydro -1H-benzazepine] (OPC-31260) improves the impaired water excretion in rats with experimental liver cirrhosis. Male Wistar rats weighing 200 to 250 g were injected in an equal volume (4 ml/kg) of carbon tetrachl oride and olive oil at an interval of seven days for three months, cau sing liver cirrhosis with ascites. Control rats were injected with onl y olive oil. Body weight (body wt) and hematocrit (Hct) were lower in the cirrhotic rats than the control rats (body wt 360.7 vs. 238.5 g, P < 0.01; Hct 46.3 vs. 39.2%, P < 0.01). A water loading test (30 ml/kg ) was carried out and 20-minute urine collections were made for three hours. The percent of water load excreted was 62.5% in the cirrhotic r ats, a value significantly less than that of 102.1% in the control rat s. However, its percent increased to 215.1% after the oral administrat ion of 5 mg/kg OPC-31260 (P < 0.01). Minimal urinary osmolality (U-Osm ) was 185.5 mOsm/kg H2O in the cirrhotic rats receiving the vehicle, a value greater than the control rats of 125.5 mOsm/kg H2O (P < 0.01). The oral administration of 5 mg/kg OPC 31260 reduced minimal U-Osm to 85.2 mOsm/kg H2O in the cirrhotic rats (P < 0.01). Urinary excretion o f sodium was lower in the cirrhotic rats than the control rats (87.1 v s. 312.4 mu Eq/3 hr, P < 0.01). The cirrhotic rats had lower GFR than the controls (2.2 vs. 2.9 ml/min, P < 0.05). Plasma AVP levels in the cirrhotic rats were 4.2 pg/ml, a value greater than the control rats o f 1.7 pg/ml (P < 0.01). Plasma AVP levels were reduced to 2.4 pg/ml in the cirrhotic rats 60 minutes after the water load, while they were s uppressed to 0.9 pg/ml in the control rats. These results indicate tha t the unsuppressible secretion of AVP is involved in the impaired wate r excretion in the cirrhotic rats and that the orally effective, non-p eptide AVP antagonist OPC-31260 is an effective therapeutic for the wa ter retention in decompensated liver cirrhosis.