Akuzawa N, Nakamura T, Kurashina T, Saito Y, Hoshino J, Sakamoto H, Sumino H, Ono Z, Nagai R
Second Department of Internal Medicine, Gunma University School of Medicine, Maebashi, Japan.
Am J Hypertens. 1998 Jun;11(6 Pt 1):697-707. doi: 10.1016/s0895-7061(98)00051-x.
We investigated the ability of the angiotensin converting enzyme (ACE) inhibitor imidapril hydrochloride, and of the calcium channel blocker amlodipine besilate, to prevent nephrosclerosis and left ventricular hypertrophy (LVH) in rats with hypertension induced by chronic inhibition of nitric oxide (NO). Male Wistar rats were given distilled water (control), NG-nitro-L-arginine methyl ester (L-NAME) 500 mg/L, L-NAME plus imidapril 10 mg/L or 100 mg/L, or L-NAME plus amlodipine 50 mg/L or 100 mg/L in the drinking water (n = 10-12). We then collected 24-h urine samples at 2, 4, and 6 weeks, obtained blood samples at 6 weeks, and histologically examined the kidney and heart. L-NAME markedly reduced the levels of NO metabolites in serum and urine while increasing the tail-cuff blood pressure, the urinary albumin level (1.90 +/- 0.65 v 0.05 +/- 0.02 mg/day/100 g in control), and the area of the left ventricular wall (83.3 +/- 3.0 v 69.8 +/- 1.8 mm2 in control). Nephrosclerosis and myocardial interstitial fibrosis were documented histologically. The plasma renin activity was significantly higher in rats treated with L-NAME than in the control rats. The concomitant administration of imidapril (10 mg/L) with L-NAME completely normalized the tail-cuff pressure, the LVH (70.8 +/- 1.8 mm2), the albuminuria (0.05 +/- 0.01 mg/day/100 g), and the histologic changes. Amlodipine (50 mg/L) also ameliorated the L-NAME-induced effects, but to a lesser extent. Thus, the chronic inhibition of NO synthesis in rats produced nephrosclerosis and LVH that were effectively prevented by giving imidapril at a dose lower than that of amlodipine. We conclude that ACE inhibitors can prevent nephrosclerosis and LVH even in the presence of a reduction in NO production, implying that in rats the inhibition of the renin-angiotensin system is more effective than the blockade of calcium channels in preventing hypertensive tissue injury.
我们研究了血管紧张素转换酶（ACE）抑制剂盐酸咪达普利和钙通道阻滞剂苯磺酸氨氯地平对慢性抑制一氧化氮（NO）诱导的高血压大鼠肾硬化和左心室肥厚（LVH）的预防作用。将雄性Wistar大鼠分为以下几组，分别给予蒸馏水（对照组）、500 mg/L的NG-硝基-L-精氨酸甲酯（L-NAME）、L-NAME加10 mg/L或100 mg/L的咪达普利、或L-NAME加50 mg/L或100 mg/L的氨氯地平，通过饮用水给药（每组n = 10 - 12）。然后在第2、4和6周收集24小时尿液样本，在第6周采集血样，并对肾脏和心脏进行组织学检查。L-NAME显著降低了血清和尿液中NO代谢产物的水平，同时升高了尾袖血压、尿白蛋白水平（对照组为0.05±0.02 mg/天/100 g，L-NAME组为1.90±0.65 mg/天/100 g）以及左心室壁面积（对照组为69.8±1.8 mm²，L-NAME组为83.3±3.0 mm²）。组织学检查证实了肾硬化和心肌间质纤维化。L-NAME处理的大鼠血浆肾素活性显著高于对照组大鼠。L-NAME与咪达普利（10 mg/L）联合给药可使尾袖血压、LVH（70.8±1.8 mm²）、蛋白尿（0.05±0.01 mg/天/100 g）以及组织学改变完全恢复正常。氨氯地平（50 mg/L）也改善了L-NAME诱导的效应，但程度较小。因此，大鼠体内NO合成的慢性抑制会导致肾硬化和LVH，而给予低于氨氯地平剂量的咪达普利可有效预防这些情况。我们得出结论，即使在NO生成减少的情况下，ACE抑制剂也能预防肾硬化和LVH，这意味着在大鼠中，抑制肾素-血管紧张素系统在预防高血压组织损伤方面比阻断钙通道更有效。
