The Therapeutic Efficacy of VP-343, a Selective Vasopressin V₂ Receptor Antagonist, in the Experimental SIADH Rat Model

Abstract

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 or chloride, calcium, and total cholesterol.These results indicate that VP-343 has efficacy to normalize the abnormalities in DDAVP-induced SIADH.