Department of Preclinical Drug Discovery, Faculty of Pharmacy, University of Montreal, Montréal, Québec, Canada.
Hypertens Res. 2012 Jun;35(6):604-10. doi: 10.1038/hr.2012.2. Epub 2012 Feb 9.
Angiotensin converting enzyme (ACE) inhibitors reduce left ventricular (LV) hypertrophy and cardiovascular-renal fibrosis. Experimentally, changes in the LV and kidney persist even after cessation of treatment. The present study investigates whether brief ACE inhibition in spontaneously hypertensive rats (SHR) provides long-term protection against the LV and kidney damage induced by the nitric oxide synthase inhibitor N-ω-nitro-L-arginine-methyl ester (L-NAME). SHR received the ACE inhibitor enalapril (n = 36) or tap water (n = 36). In all, 12 control and treated SHR were sacrificed after 2 weeks and remaining rats were taken off-treatment. After a 2-week washout, 12 controls or previously treated SHR were sacrificed and remaining rats were treated with L-NAME ((control (Con)+L, enalapril (Enal)+L) for 10 days. At sacrifice, blood pressure was recorded via carotid artery cannulation in anesthetized rats, and blood, the kidney and LV were isolated for analysis. LV mass and arterial pressure were significantly reduced by enalapril. LV mass showed a persistent reduction throughout the study. In LV, prior enalapril treatment provided significant (P<0.05) protection against L-NAME-induced increases in proliferating cells (Con+L: 11 ± 10.0 mm(2) vs. Enal+L: 4 ± 4.4 mm(2)), interstitial fibrosis (Con+L: 3 ± 2.5% vs. Enal+L: 1 ± 1.0%) and tissue macrophages (Con+L: 12 ± 9 mm(2) vs. Enal+L: 5 ± 3.6 mm(2)). In the kidney, prior enalapril treatment protected against L-NAME-induced interstitial fibrosis and vascular injury. There was no difference in glomerular size or glomerulosclerosis regardless of prior treatment. Plasma creatinine and urea were significantly increased in L-NAME treated rats. This study suggests that brief ACE inhibition confers protection against future heart and kidney injury, even in the absence of continued antihypertensive treatment.
血管紧张素转换酶（ACE）抑制剂可减少左心室（LV）肥大和心血管-肾纤维化。实验表明，即使停止治疗后，LV 和肾脏的变化仍会持续。本研究旨在探讨短暂的 ACE 抑制是否可以为自发性高血压大鼠（SHR）提供长期保护，防止一氧化氮合酶抑制剂 N-ω-硝基-L-精氨酸甲酯（L-NAME）引起的 LV 和肾脏损伤。SHR 接受 ACE 抑制剂依那普利（n = 36）或自来水（n = 36）治疗。总共，2 周后处死 12 只对照和治疗 SHR，其余大鼠停药。洗脱 2 周后，处死 12 只对照或先前治疗的 SHR，并对其余大鼠给予 L-NAME（对照（Con）+L、依那普利（Enal）+L）治疗 10 天。在处死时，通过麻醉大鼠的颈动脉插管记录血压，并分离血液、肾脏和 LV 进行分析。依那普利显著降低 LV 质量和动脉压。LV 质量在整个研究过程中持续降低。在 LV 中，先前的依那普利治疗可显著（P<0.05）防止 L-NAME 引起的增殖细胞增加（Con+L：11 ± 10.0 mm² vs. Enal+L：4 ± 4.4 mm²）、间质纤维化（Con+L：3 ± 2.5% vs. Enal+L：1 ± 1.0%）和组织巨噬细胞（Con+L：12 ± 9 mm² vs. Enal+L：5 ± 3.6 mm²）。在肾脏中，先前的依那普利治疗可防止 L-NAME 引起的间质纤维化和血管损伤。无论先前是否治疗，肾小球大小或肾小球硬化均无差异。L-NAME 治疗大鼠的血浆肌酐和尿素显著升高。本研究表明，短暂的 ACE 抑制可提供针对未来心脏和肾脏损伤的保护，即使在没有持续降压治疗的情况下也是如此。
