Juxtaglomerular cell hypertrophy and hyperplasia induced in rhesus monkeys by angiotensin II receptor antagonists.
BACKGROUND
Juxtaglomerular (JG) cell hypertrophy and hyperplasia were investigated in rhesus monkeys given angiotensin II (AII) AT1 receptor antagonists L-158,338 and DUP 753 (MK-0954, losartan).


METHODS
In 2 initial studies, L-158,338 was given orally at 10, 30, and 90 mg/kg/day for 3 or 14 weeks. To investigate the observed JG hypertrophy and hyperplasia, in a third 5-week experiment L-158,338 was given alone at 90 mg/kg/day, or with physiologic saline supplementation at 25 ml/kg/day, or coadministered with the angiotensin converting enzyme inhibitor enalapril at 10 mg/kg/day. Physiologic saline was given to attempt to suppress renin release through volume expansion and/or sodium retention. Enalapril was given to lower plasma AII levels and observe whether JG cell hypertrophy and hyperplasia were increased or decreased. For comparison, DUP 753 was given at 90 and 300 mg/kg/day. Plasma renin activity and AII concentration were measured in this study.


RESULTS
Dose- and time-dependent increases in JG cell hypertrophy and hyperplasia were seen in the 2 initial experiment. In the third experiment, plasma renin activity and AII concentration were increased 3-fold and 6-fold over pretest values by L-158,338 at 90 mg/kg/day for 5 weeks. Saline supplementation had no effect on these parameters but diminished the group mean severity grade for JG hypertrophy and hyperplasia from 1.5 to 1.0. Enalapril coadministration had no effect on plasma renin activity, whereas it blunted the plasma AII increase caused by L-158,338 and increased the group mean grade to 2.5. DUP 753 at 300 mg/kg/day produced similar increases in plasma renin activity and AII concentration but only resulted in grade 1 JG cell hypertrophy and hyperplasia.


CONCLUSIONS
L-158,338-induced JG cell hypertrophy and hyperplasia is an exaggerated pharmacologic response that can be modulated by saline supplementation and angiotensin converting enzyme inhibition. These results suggest that decreased renal perfusion or altered sodium homeostasis and plasma AII concentration are important variables that contribute to AT1 receptor blockade to induce JG cell hypertrophy and hyperplasia.
Department of Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania.
R A
RA
Owen
S
S
Molon-Noblot
M F
MF
Hubert
P K
PK
Siegl
R S
RS
Eydelloth
K P
KP
Keenan
D000804:Angiotensin II / Q000097:blood; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000009:adverse effects / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004656:Enalapril / Q000494:pharmacology; D006965:Hyperplasia / Q000097:blood / Q000139:chemically induced / Q000473:pathology; D006984:Hypertrophy / Q000097:blood / Q000139:chemically induced / Q000473:pathology; D007093:Imidazoles / Q000009:adverse effects / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology*; D007606:Juxtaglomerular Apparatus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D019808:Losartan; D008253:Macaca mulatta; D011725:Pyridines / Q000009:adverse effects / Q000494:pharmacology*; D012083:Renin / Q000097:blood; D013777:Tetrazoles / Q000009:adverse effects / Q000494:pharmacology*; D013997:Time Factors
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D007093:Imidazoles; D007166:Immunosuppressive Agents; D011725:Pyridines; D013777:Tetrazoles; D000804:Angiotensin II; C083194:L 158338; D004656:Enalapril; D012083:Renin; D019808:Losartan