The therapeutic efficacy of VP-343, a selective vasopressin V2 receptor antagonist, in the experimental SIADH rat model.
The aim of this work is to investigate the therapeutic efficacy of VP-343 ((N-[4-[[(2S,3aR)-2-hydroxy-2,3,3a,4-tetrahydropyrrolo[1,2-a]qunoxalin-5(1H)-yl]phenyl]-4'-methyl[1,1'-biphenyl]-2-carboxamide), a selective vasopressin V2 receptor antagonist, using the experimental SIADH (syndrome of inappropriate secretion of antidiuretic hormone) rat model. In the model, which was accomplished by administering continuously 1-desamino-8-D-arginine vasopressin (DDAVP), serum sodium levels (S(Na)) and serum osmolarity levels (S(Osm)) significantly and remarkably decreased, which was accompanied with hyper-osmolarity of urine and oliguria. VP-343 increased rapidly and dose-dependently S(Na) and S(Osm). VP-343 exhibited marked diuretic action and decreased urine osmolarity dose-dependently. In the SIADH rat model, all serum levels of chloride, calcium, creatinine, total cholesterol, and uric acid decreased when compared with normal levels. VP-343 increased all serum levels of chloride, calcium, and total cholesterol. These results indicate that VP-343 has efficacy to normalize the abnormalities in DDAVP-induced SIADH.
Naito
A
A
Sagami Research Laboratory, Wakamoto Pharmaceutical Co., Ltd., 378 Kanade, Ohi-machi, Ashigarakamigun, Kanagawa, Japan. a-naito@wakamoto-pharm.co.jp
Hasegawa
H
H
Kurasawa
T
T
Ohtake
Y
Y
Matsukawa
H
H
Ezure
Y
Y
Tsuriya
Y
Y
Koike
K
K
Shigenobu
K
K
D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D003894:Deamino Arginine Vasopressin / Q000494:pharmacology; D007177:Inappropriate ADH Syndrome / Q000188:drug therapy* / Q000652:urine; D008297:Male; D009994:Osmolar Concentration; D011758:Pyrroles / Q000627:therapeutic use*; D011810:Quinoxalines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012076:Renal Agents / Q000494:pharmacology; D012964:Sodium / Q000097:blood; D014554:Urination / Q000187:drug effects; D014556:Urine / Q000737:chemistry
D065092:Antidiuretic Hormone Receptor Antagonists; D011758:Pyrroles; D011810:Quinoxalines; D012076:Renal Agents; C120959:VP 343; D012964:Sodium; D003894:Deamino Arginine Vasopressin