Owen R A, Molon-Noblot S, Hubert M F, Siegl P K, Eydelloth R S, Keenan K P
Department of Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania.
Lab Invest. 1994 Oct;71(4):543-51.
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).
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.
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.
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.
研究了给予血管紧张素 II（AII）AT1 受体拮抗剂 L-158,338 和 DUP 753（MK-0954，氯沙坦）的恒河猴的球旁（JG）细胞肥大和增生情况。
在最初的两项研究中，L-158,338 按 10、30 和 90 mg/kg/天的剂量口服给药 3 或 14 周。为研究观察到的 JG 肥大和增生情况，在第三个为期 5 周的实验中，L-158,338 单独按 90 mg/kg/天给药，或补充 25 ml/kg/天的生理盐水，或与血管紧张素转换酶抑制剂依那普利按 10 mg/kg/天联合给药。给予生理盐水以试图通过容量扩张和/或钠潴留来抑制肾素释放。给予依那普利以降低血浆 AII 水平，并观察 JG 细胞肥大和增生是增加还是减少。作为对照，DUP 753 按 90 和 300 mg/kg/天给药。本研究中测量了血浆肾素活性和 AII 浓度。
在最初的两项实验中观察到 JG 细胞肥大和增生呈剂量和时间依赖性增加。在第三个实验中，L-158,338 按 90 mg/kg/天给药 5 周，使血浆肾素活性和 AII 浓度比预测试值分别增加了 3 倍和 6 倍。补充生理盐水对这些参数无影响，但使 JG 肥大和增生的组平均严重程度等级从 1.5 降至 1.0。联合给予依那普利对血浆肾素活性无影响，但它减弱了 L-158,338 引起的血浆 AII 升高，并使组平均等级升至 2.5。DUP 753 按 300 mg/kg/天给药使血浆肾素活性和 AII 浓度有类似升高，但仅导致 1 级 JG 细胞肥大和增生。
L-158,338 诱导的 JG 细胞肥大和增生是一种过度的药理反应，可通过补充生理盐水和血管紧张素转换酶抑制来调节。这些结果表明，肾灌注减少或钠稳态及血浆 AII 浓度改变是导致 AT1 受体阻断诱导 JG 细胞肥大和增生的重要变量。
