Mason R Preston, Jacob Robert F, Corbalan J Jose, Kaliszan Roman, Malinski Tadeusz
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Am J Hypertens. 2014 Mar;27(3):482-8. doi: 10.1093/ajh/hpt202. Epub 2013 Oct 29.
Clinical trials have shown that amlodipine reduces cardiovascular events at a rate that is not predicted by changes in brachial arterial pressure alone. These findings may be explained, in part, by the pleiotropic effects of amlodipine on endothelial cell (EC) function. In this study, we elucidated the effect of amlodipine on nitric oxide (NO) bioavailability and cytotoxic peroxynitrite (ONOO(-)) and blood pressure (BP).
Spontaneously hypertensive rats (SHRs) were treated with vehicle or amlodipine (5 mg/kg/day) for 8 weeks and compared with untreated, baseline rats. NO and ONOO(-) release from aortic and glomerular ECs were measured ex vivo using amperometric nanosensors following maximal stimulation with calcium ionophore. BP was measured using the tail-cuff method.
As compared with baseline, vehicle treatment had reduced aortic endothelial NO release from 157 ± 11 nM to 55 ± 6 nM and increased ONOO(-) from 69 ± 7 nM to 156 ± 19 nM. The NO/ONOO(-) ratio, a comprehensive measurement of eNOS function, decreased from 2.3 ± 0.3 to 0.3 ± 0.1. Compared with vehicle, amlodipine treatment restored NO to 101 ± 3 nM, decreased ONOO(-) to 50 ± 4 nM, and increased the NO/ONOO(-) ratio to 2.0 ± 0.2, a level similar to baseline. Similar changes were observed for glomerular ECs. Mean arterial blood pressure increased from 149 ± 3 mm Hg (baseline) to 174 ± 1 mm Hg (vehicle). Amlodipine slightly, but significantly, decreased mean arterial blood pressure to 167 ± 3 mm Hg vs. vehicle treatment.
Amlodipine increased NO bioavailability and decreased nitroxidative stress in SHRs with EC dysfunction disproportionately to BP changes. These direct, vascular effects of amlodipine on EC function may contribute to reduced risk for atherothrombotic events as observed in clinical trials.
临床试验表明，氨氯地平降低心血管事件的速率并非仅由肱动脉血压变化所预测。这些发现可能部分归因于氨氯地平对内皮细胞（EC）功能的多效性作用。在本研究中，我们阐明了氨氯地平对一氧化氮（NO）生物利用度、细胞毒性过氧亚硝酸盐（ONOO⁻）和血压（BP）的影响。
自发性高血压大鼠（SHR）接受载体或氨氯地平（5mg/kg/天）治疗8周，并与未治疗的基线大鼠进行比较。在用钙离子载体进行最大刺激后，使用安培纳米传感器离体测量主动脉和肾小球EC释放的NO和ONOO⁻。使用尾袖法测量血压。
与基线相比，载体治疗使主动脉内皮NO释放量从157±11nM降至55±6nM，并使ONOO⁻从69±7nM增加至156±19nM。作为eNOS功能的综合测量指标，NO/ONOO⁻比值从2.3±0.3降至0.3±0.1。与载体相比，氨氯地平治疗使NO恢复至101±3nM，使ONOO⁻降至50±4nM，并使NO/ONOO⁻比值增加至2.0±0.2，这一水平与基线相似。在肾小球EC中观察到类似变化。平均动脉血压从149±3mmHg（基线）升至174±1mmHg（载体）。氨氯地平使平均动脉血压略有但显著降低，与载体治疗相比降至167±3mmHg。
在伴有EC功能障碍的SHR中，氨氯地平增加了NO生物利用度并降低了氧化亚氮应激，且这种作用与血压变化不成比例。氨氯地平对EC功能的这些直接血管作用可能有助于降低临床试验中观察到的动脉粥样硬化血栓形成事件的风险。
