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 recepto r antagonists L-158,338 and DUP 753 (MK-0954, losartan). EXPERIMENTAL DESIGN: In 2 initial studies, L-158,338 was given orally at 10, 30, an d 90 mg/kg/day for 3 or 14 weeks. To investigate the observed JG hyper trophy and hyperplasia, in a third 5-week experiment L-158,338 was giv en alone at 90 mg/kg/day, or with physiologic saline supplementation a t 25 ml/kg/day, or coadministered with the angiotensin converting enzy me inhibitor enalapril at 10 mg/kg/day. Physiologic saline was given t o attempt to suppress renin release through volume expansion and/or so dium retention. Enalapril was given to lower plasma An levels and obse rve whether JG cell hypertrophy and hyperplasia were increased or decr eased. For comparison, DUP 753 was given at 90 and 300 mg/kg/day. Plas ma renin activity and AII concentration were measured in this study. R ESULTS: Dose- and time-dependent increases in JG cell hypertrophy and hyperplasia were seen in the 2 initial experiment. In the third experi ment, plasma renin activity and AII concentration were increased 3-fol d and 6-fold over pretest values by L-158,338 at 90 mg/kg/day for 5 we eks. Saline supplementation had no effect on these parameters but dimi nished the group mean severity grade for JG hypertrophy and hyperplasi a 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 con centration but only resulted in grade 1 JG cell hypertrophy and hyperp lasia. CONCLUSIONS: L-158,338-induced JG cell hypertrophy and hyperpla sia is an exaggerated pharmacologic response that can be modulated by saline supplementation and angiotensin converting enzyme inhibition. T hese 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.