Histopathological and Ultrastructural Changes in the Juxtaglomerular Apparatus of the Rat Following Administration of ZENECA ZD6888 (2-ethyl-5,6,7,8-tetrahydro-4-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)-methoxylquinoline), an Angiotensin II Antagonist

Abstract

Male and female Alderley Park rats were treated for 26 wk with ZENECA ZD6888, an angiotensin II (All) antagonist, at doses of 25, 50, and 250 mg/kg/day and the kidneys examined by light and electron microscopy. Nephropathy (tubular degeneration and regeneration), thickening of the basal lamina, mononuclear cell infiltration, and hypertrophy and hyperplasia of the juxtaglomerular apparatus were seen by light microscopy. Ultrastructurally, juxtaglomerular cell granules were increased in number and displayed substantial structural heterogeneity. In some cells, granules contained paracrystalline inclusions while others consisted predominantly of myelinic debris. Evidence ofconversion of arteriolar smooth muscle cells into juxtaglomerular cells and their degeneration was also obtained by electron microscopy. The juxtaglomerular changes were treatment- and dose-related and were attributed to an exaggerated pharmacological action of the compound, that is, ZD6888-mediated blockade of All receptors leading to competitive inhibition of the All-mediated release of renin. The resemblance between the findings seen in the present study following administration of an All antagonist and those due to angiotensin-converting enzyme inhibitors reported by others was striking.