Histopathological Study of Kidney Abnormalities in an Experimental SIADH Rat Model and Its Application on the Evaluation of the Pharmacologic Profile of VP-343, a Selective Vasopressin V_2 Receptor Antagonist

摘要

The aim of this work was to investigate histopathologically the relationship between the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and kidney abnormalities and 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 V_2 receptor antagonist, in an experimental SIADH rat model. In the model, which was prepared by continuously administering 1-desamino-8-D-arginine vasopressin (DDAVP), histopathologic abnormalities, such as dilatation of tubules, basophilic changes in tubules, inflammatory cell infiltration, and mineralization were found in the kidney, accompanied by significant increases in the relative weight of the kidney, lung, liver, adrenal gland, and heart. VP-343 was shown to be effective in protecting the kidney from the histopathologic abnormalities and to normalize the relative weight of the kidney and several common pathophysiologic features, such as hyponatremia, hyposmolarity of plasma, hyperosmolarity of urea, and oligurea, as described previously. These results demonstrate the occurrence of histopathologic abnormalities in the kidney and the efficacy of VP-343 in improving abnormalities in the DDAVP-induced SIADH rat model.