THERAPEUTIC EFFICACY OF NONPEPTIDE ADH ANTAGONIST OPC-31260 IN SIADH RATS

The present study was undertaken to determine whether the non-peptide V2 antidiuretic hormone (ADH) antagonist 5-dimethylamino-1{4-(2-methylbenzoylamino)benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (OPC-31260) normalized hyponatremia in rats with an experimental syndrome of inappropriate secretion of ADH (SIADH). Rats were administered V2 agonist 1-deamino-8-D-arginine vasopressin (DDAVP) subcutaneously at a rate of 5 ng/hr using an osmotic minipump and a 40 ml/day liquid diet. Serum sodium levels (S(Na)) and serum osmolality (S(Osm)) markedly decreased to 119 mEq/liter and 249 mOsm/kg H2O, respectively, 48 hours after the start of dDAVP administration. Hyponatremia persisted in a similar magnitude during the observation period of 14 days. On days 7 to 13 OPC-31260, administered 5 mg/kg per day orally, promptly raised S(Na) and S(Osm) to 134 mEq/liter and 282 mOsm/kg H2O in half a day, respectively, followed by the normalization of S(Na) and S(Osm) during the rest of the observation period. The cease of administration of OPC-31260 again decreased S(Na) and S(Osm) in rats receiving dDAVP. In contrast, S(Na) and S(Osm) were within the normal values in rats receiving 0.15 M NaCl, a vehicle for dDAVP, in the presence or absence of OPC-31260, The administration of OPC-31260 promptly caused marked water diuresis on day 7 in the hyponatremic rats receiving dDAVP, namely 5 mg/kg OPC-31260 markedly increased urinary volume and decreased U(Osm). These results indicate that there is dilutional hyponatremia in rats receiving dDAVP and 40 ml/day liquid diets, and that OPC-31260 is an effective therapeutic for hyponatremia associated with dDAVP-induced SIADH.