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)- methoxy]quinoline), an angiotensin II antagonist.
Male and female Alderley Park rats were treated for 26 wk with ZENECA ZD6888, an angiotensin II (AII) 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 of conversion 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 AII receptors leading to competitive inhibition of the AII-mediated release of renin. The resemblance between the findings seen in the present study following administration of an AII antagonist and those due to angiotensin-converting enzyme inhibitors reported by others was striking.
Jackson
D G
DG
Safety of Medicines Department, ZENECA Pharmaceuticals, Macclesfield, Cheshire, United Kingdom.
Jones
H B
HB
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000633:toxicity; D000818:Animals; D001160:Arterioles; D001713:Biphenyl Compounds / Q000633:toxicity*; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000648:ultrastructure; D005260:Female; D002479:Inclusion Bodies / Q000648:ultrastructure; D007606:Juxtaglomerular Apparatus / Q000187:drug effects* / Q000648:ultrastructure; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008297:Male; D011804:Quinolines / Q000633:toxicity*; D051381:Rats
D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D011804:Quinolines; D000804:Angiotensin II; C081117:ICI D6888