Histopathological Study of Kidney Abnormalities in an Experimental SIADH Rat Model and Its Application to the Evaluation of the Pharmacologic Profile of VP-343, a Selective Vasopressin V2 Receptor Antagonist

• Published in: Biological & pharmaceutical bulletin 2001, Vol.24(8), pp.897-901
• Main Authors: NAITO, Akira, HASEGAWA, Hisashi, KURASAWA, Takashi, OHTAKE, Yasuhiro, MATSUKAWA, Hidehiko, EZURE, Yohji, KOIKE, Katsuo, SHIGENOBU, Koki
• Format: Article
• Language: English
• Subjects: Animals; Antidiuretic Hormone Receptor Antagonists; Biological and medical sciences; Deamino Arginine Vasopressin; Diuretics - pharmacology; Diuretics - therapeutic use; Glomerulonephritis; Histocytochemistry; histopathology; Inappropriate ADH Syndrome - chemically induced; Inappropriate ADH Syndrome - drug therapy; Inappropriate ADH Syndrome - pathology; kidney; Kidney - pathology; Male; Medical sciences; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Organ Size - drug effects; Osmolar Concentration; Pharmacology. Drug treatments; Pyrroles - pharmacology; Pyrroles - therapeutic use; Quinoxalines - pharmacology; Quinoxalines - therapeutic use; Rats; Rats, Sprague-Dawley; Renal Agents; SIADH; Sodium - blood; Urinary system; Urodynamics - drug effects; vasopressin; VP-343
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.24.897

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 V2 receptor antagonist, in an experimental SIADH rat model. In the model, which was prepared by continuously administering 1-desamino-8-D-arginine vasopression (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.