Therapeutic efficacy of non-peptide 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 (SNa) and serum osmolality (SOsm) 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 SNa and SOsm to 134 mEq/liter and 282 mOsm/kg H2O in half a day, respectively, followed by the normalization of SNa and SOsm during the rest of the observation period. The cease of administration of OPC-31260 again decreased SNa and SOsm in rats receiving dDAVP. In contrast, SNa and SOsm 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 UOsm. 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.
Fujisawa
G
G
Department of Medicine, Jichi Medical School, Tochigi, Japan.
Ishikawa
S
S
Tsuboi
Y
Y
Okada
K
K
Saito
T
T
D000818:Animals; D001552:Benzazepines / Q000627:therapeutic use*; D003894:Deamino Arginine Vasopressin; D007010:Hyponatremia / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy; D007177:Inappropriate ADH Syndrome / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D009994:Osmolar Concentration; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000097:blood; D014667:Vasopressins / Q000037:antagonists & inhibitors*
D001552:Benzazepines; D014667:Vasopressins; C076251:mozavaptan; D012964:Sodium; D003894:Deamino Arginine Vasopressin