Histopathological study of kidney abnormalities in an experimental SIADH rat model and its application to the evaluation of the pharmacologic profileof VP-343, a selective vasopressin V-2 receptor antagonist

The aim of this work was to investigate histopathologically the relationshi p between the syndrome of inappropriate secretion of antidiuretic hormone ( SIADH) and kidney abnormalities and the therapeutic efficacy of VP-343 ((N- [4-[[(2S,3a-R)-2-hydroxy-2,3,3a,4-tetrahydropyrrolo[1,2-a]qunoxalin-5(1H)-y l]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 va sopressin (DDAVP), histopathologic abnormalities, such as dilatation of tub ules, basophilic changes in tubules, inflammatory cell infiltration, and mi neralization were found in the kidney, accompanied by, significant increase s in the relative weight of the kidney, lung, liver, adrenal gland, and hea rt. VP-343 was shown to be effective in protecting the kidney from the hist opathologic abnormalities and to normalize the relative weight of the kidne y and several common pathophysiologic features, such as hyponatremia, hypos molarity of plasma, hyperosmolarity of urea, and oligurea, as described pre viously. These results demonstrate the occurrence of histopathologic abnormalities i n the kidney and the efficacy of VP-343 in improving abnormalities in the D DAVP-induced SIADH rat model.