The morphology of juxtaglomerular cell hyperplasia and hypertrophy in normotensive rats and monkeys given an angiotensin II receptor antagonist.
L-694,492 (DUP 532), an angiotensin II (AII) receptor antagonist, was given orally at 125 mg/kh/day to rats and monkeys for up to 6 mo to assess the effects of the compound on juxtaglomerular (JG) cells. In rats, mild JG cell hypertrophy/hyperplasia occurred and was associated with a 12-fold increase in the bromodeoxyuridine-labeling index of JG cells and a 10-fold increase in renal renin content. Ultrastructurally, intermediate cells with characteristics of both smooth muscle cells and granulated renin-producing cells as well as hypertrophied renin-synthesizing cells were seen in the afferent arterioles. In monkeys, marked hypertrophy and hyperplasia were seen with an 80% increase in JG cell numbers, mitotic activity, and a greatly increased renin content compared to controls. Three mo after drug withdrawal, an increased number of cells remained, which showed features of smooth muscle cells with essentially no renin. These results show that AII receptor antagonism stimulates increased renal renin production by hypertrophy of existing granulated cells, metaplasia of smooth muscle cells to renin-synthesizing cells, and cell proliferation. When treatment was discontinued, the renin-producing cells redeveloped the features of smooth muscle cells, but, as we have shown with enalapril (augioteusin-converting enzyme inhibitor), the increase in their number persists for at least 3 mo.
Owen
R A
RA
Merck Sharp & Dohme-Chibret Laboratories, Department of Safety Assessment, Riom, France.
Molon-Noblot
S
S
Hubert
M F
MF
Kindt
M V
MV
Keenan
K P
KP
Eydelloth
R S
RS
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D004261:DNA Replication / Q000502:physiology; D005260:Female; D006965:Hyperplasia / Q000139:chemically induced / Q000473:pathology; D006984:Hypertrophy / Q000139:chemically induced / Q000473:pathology; D007093:Imidazoles / Q000633:toxicity*; D007124:Immunoenzyme Techniques; D007606:Juxtaglomerular Apparatus / Q000187:drug effects* / Q000473:pathology* / Q000648:ultrastructure; D008253:Macaca mulatta; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000032:analysis; D013777:Tetrazoles / Q000633:toxicity*; D005466:Fluorocarbons
D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D012083:Renin; D013777:Tetrazoles; C069045:DuP 532; D005466:Fluorocarbons