Therapeutic effects of tolvaptan, a potent, selective nonpeptide vasopressin V2 receptor antagonist, in rats with acute and chronic severe hyponatremia.
The therapeutic efficacy of tolvaptan (OPC-41061), a potent, selective nonpeptide vasopressin V(2) receptor antagonist, on acute and chronic severe hyponatremia was assessed in rats. Experiments were designed to demonstrate the efficacy of tolvaptan reducing mortality in an acute model, and controlling the extent of serum sodium elevation without causing abnormal animal behavior suggesting neurological symptoms in a chronic model. In the acute model, rats developed rapidly progressive, severe hyponatremia by continuous sc infusion of [deamino-Cys(1), D-Arg(8)]-vasopressin (10 ng/h) and forced water-loading (additional 10% initial body weight per day). By d 6, untreated rats had a 47% mortality rate. However, rats treated with repeated oral administrations of tolvaptan (1, 3, and 10 mg/kg) produced dose-dependent aquaresis (i.e. urine volume increased and urine osmolality decreased) that resulted in a gradual increase in plasma sodium concentration. Consequently, tolvaptan treatment reduced mortality and, at higher doses, resulted in no observed deaths. In the gradual model, rats receiving a continuous sc infusion of [deamino-Cys(1), D-Arg(8)]-vasopressin (1 ng/h) combined with a liquid diet were induced to stable, severe hyponatremia (approximately 110 mEq/liter), which lead to increased organ weight and water content. Rats receiving dose titrations of tolvaptan (0.25, 0.5, 1, 2, 4, and 8 mg/kg) increased plasma sodium to healthy levels without causing abnormal animal behavior suggesting neurological symptoms or death, improved hyponatremia-driven increases in wet weight and water content in the organs. Thus, in animal models, analogous to the hyponatremia forms seen in humans, tolvaptan presents exciting therapeutic implications in the management of patients with severe hyponatremia.
Miyazaki
Toshiki
T
Research Institute of Pharmacological and Therapeutical Development, Otsuka Pharmaceutical Co., Ltd., Kawauchi-cho, Tokushima 771-0192, Japan. t_miyazaki@research.otsuka.co.jp
Yamamura
Yoshitaka
Y
Onogawa
Toshiyuki
T
Nakamura
Shigeki
S
Kinoshita
Shizuo
S
Nakayama
Sunao
S
Fujiki
Hiroyuki
H
Mori
Toyoki
T
D000208:Acute Disease; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000494:pharmacology*; D001834:Body Water / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002908:Chronic Disease; D004231:Diuresis / Q000187:drug effects; D007010:Hyponatremia / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D012964:Sodium / Q000378:metabolism; D000077602:Tolvaptan; D014556:Urine / Q000737:chemistry
D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D000077602:Tolvaptan; D012964:Sodium