Jia L, Blantz R C
Division of Nephrology-Hypertension, University of California, San Diego School of Medicine, Veterans Affairs Medical Center, 92161, USA.
Eur J Pharmacol. 1998 Jul 31;354(1):33-41. doi: 10.1016/s0014-2999(98)00424-5.
The present investigation was performed to evaluate the effects of S-nitrosocaptopril, a novel vasodilator possessing the capacities of both an angiotensin converting enzyme inhibitor and an NO donor, on blood pressure and renal function in rats. S-nitrosocaptopril produced acute reductions in mean arterial pressure after both oral dosing (5, 10, 50 mg/kg) to chronically-catheterized awake rats and intravenous administrations (0.125, 1.25, 12.5 mg/kg) to anesthetized rats. The hypotensive magnitude and duration of S-nitrosocaptopril were dose-dependent. Acute pressure-associated reductions in the glomerular filtration rate and urine flow were observed only at high concentration of S-nitrosocaptopril (12.5 mg/kg, i.v.) in both awake and anesthetized rats. These decreases were transient, followed by an overshoot of glomerular filtration rate and urine flow above basal values. In contrast, captopril (i.v.) did not produce any significant acute effects on mean blood pressure and glomerular filtration rate in either awake or anesthetized rats. In rats with acute hypertension induced by NG-monomethyl-L-arginine (L-NMMA, 30 mg/kg, i.v.), S-nitrosocaptopril (0.125 mg/kg, i.v.) significantly abolished the hypertensive effects. In contrast, the hypertension was not affected by captopril. In two-kidney one-clipped Goldblatt hypertensive rats, oral administration of S-nitrosocaptopril (25 mg/kg, b.i.d.) for 10 days significantly reduced systolic blood pressure and preserved glomerular filtration rate. The oral antihypertensive effect of S-nitrosocaptopril was more potent than captopril (P < 0.05). In conclusion, these findings indicate that: (1) S-nitrosocaptopril provides both acute and chronic anti-hypertensive effects orally and intravenously, whereas captopril has only moderate chronic oral effects; and (2) S-nitrosocaptopril preferentially decreases blood pressure without markedly affecting glomerular filtration rate.
本研究旨在评估新型血管扩张剂S-亚硝基卡托普利对大鼠血压和肾功能的影响，该药物兼具血管紧张素转换酶抑制剂和一氧化氮供体的功能。给慢性插管清醒大鼠口服给药（5、10、50mg/kg）以及给麻醉大鼠静脉注射（0.125、1.25、12.5mg/kg）后，S-亚硝基卡托普利均能使平均动脉压急性降低。S-亚硝基卡托普利的降压幅度和持续时间呈剂量依赖性。仅在清醒和麻醉大鼠中给予高浓度的S-亚硝基卡托普利（12.5mg/kg，静脉注射）时，才观察到与压力相关的肾小球滤过率和尿流急性降低。这些降低是短暂的，随后肾小球滤过率和尿流会超过基础值。相比之下，卡托普利（静脉注射）对清醒或麻醉大鼠的平均血压和肾小球滤过率均未产生任何显著的急性影响。在由NG-单甲基-L-精氨酸（L-NMMA，30mg/kg，静脉注射）诱导急性高血压的大鼠中，S-亚硝基卡托普利（0.125mg/kg，静脉注射）能显著消除高血压作用。相比之下，卡托普利对高血压无影响。在二肾一夹型戈德布拉特高血压大鼠中，口服S-亚硝基卡托普利（25mg/kg，每日两次）10天可显著降低收缩压并维持肾小球滤过率。S-亚硝基卡托普利的口服降压作用比卡托普利更强（P<0.05）。总之，这些研究结果表明：（1）S-亚硝基卡托普利经口服和静脉给药均具有急性和慢性降压作用，而卡托普利仅具有中度的慢性口服作用；（2）S-亚硝基卡托普利优先降低血压，而对肾小球滤过率无明显影响。
