Ultrastructural juxtaglomerular cell changes in normotensive rats treated with quinapril, an inhibitor of angiotensin-converting enzyme.
Sequential histologic and ultrastructural changes in juxtaglomerular apparatus (JGA) were defined in male rats treated with quinapril, an inhibitor of angiotensin-converting enzyme (ACE). Doses of 0, 10, 100, and 400 mg/kg were administered daily by gavage for up to 4 weeks. Granular juxtaglomerular (JG) cells were normal or hypogranular on Day 1 at all doses and were hypergranular by Day 7 in rats given 100 and 400 mg/kg relative to age-matched controls. Histologically, JGA hypertrophy was apparent by Day 7 at all doses and was most pronounced by Day 14 in intermediate and deep cortical zones of rats given 100 and 400 mg/kg. Ultrastructurally, hypertrophic JG cells had abundant rough endoplasmic reticulum and free ribosomes, and prominent Golgi complexes associated with numerous cytoplasmic coated vesicles. Dose-dependent increases in numbers of protogranules, altered granules, and cytoplasmic vacuoles occurred in association with decreased size and increased pleomorphism of mature secretory granules. Granule alterations included vesicular to lamellar membranous matrical inclusions, irregular patterns of osmiophilia, matrical vacuolation, and flocculent to coarsely granular matrix of greater density than mature granules. We concluded that JG cell hypertrophy and hyperplasia occurred rapidly in response to subchronic ACE inhibition. Further, ultrastructural changes in JG cells were indicative of stimulated renin synthesis by a regulated pathway, renin secretion by exocytosis and cytoplasmic solubilization of granules, and autophagy of granules as a mechanism whereby JG cells regulate levels of stored renin under conditions of excessive stimulation.
Dominick
M A
MA
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Co., Ann Arbor, Michigan 48105.
Bobrowski
W F
WF
Metz
A L
AL
Gough
A W
AW
MacDonald
J R
JR
D000804:Angiotensin II / Q000502:physiology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000633:toxicity*; D000818:Animals; D006965:Hyperplasia; D006984:Hypertrophy; D007546:Isoquinolines / Q000633:toxicity*; D007606:Juxtaglomerular Apparatus / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D000077583:Quinapril; D051381:Rats; D011919:Rats, Inbred Strains; D044005:Tetrahydroisoquinolines
D000806:Angiotensin-Converting Enzyme Inhibitors; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D000804:Angiotensin II; D000077583:Quinapril