Azelnidipine has anti-atherosclerotic effects independent of its blood pressure-lowering actions in monkeys and mice
Azelnidipine has anti-atherosclerotic effects independent of its blood pressure-lowering actions in monkeys and mice
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DOI：
10.1016/j.atherosclerosis.2007.03.036
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发表时间：
2008-01-01
期刊：
影响因子：
5.3
通讯作者：
Sunagawa, Kenji
中科院分区：
文献类型：
--
作者：
Nakano, Kaku;Egashira, Kensuke;Sunagawa, Kenji
钙通道阻滞剂（CCB）已被证明可以改善动脉粥样硬化性血管疾病的临床结局。第三代钙通道阻滞剂阿折地平的血管保护作用机制尚不完全清楚。我们询问阿折地平是否在降低血压的作用之外减轻猴子和小鼠的动脉粥样硬化。食蟹猴在高胆固醇饮食4周后随机分为3组：对照组（未处理）和每日3和10 mg/kg阿折地平;这些剂量对全身动脉压或心率没有影响。通过球囊损伤在主动脉中诱导动脉粥样硬化，并继续饮食和治疗另外24周。阿折地平不影响血脂谱，但减少动脉粥样硬化的发展，如通过消除局部氧化应激和减少单核细胞趋化蛋白-1和血小板衍生生长因子的表达所检测到的。阿折地平还能抑制血管平滑肌细胞的增殖和迁移。在动脉粥样硬化ApoE基因敲除（ApoE-KO）小鼠喂养高胆固醇饮食，阿折地平，而不是降血糖降低动脉粥样硬化的发展。这两种药物都没有改变小鼠的血脂谱或收缩压。因此，阿折地平在临床相关剂量下在猴和小鼠中表现出与其降压作用无关的抗动脉粥样硬化作用，表明阿折地平可能作为“血管保护性钙通道阻滞剂”。(C)2007爱思唯尔爱尔兰有限公司保留所有权利。
Calcium channel blockers (CCBs) have been shown to improve clinical outcomes in atherosclerotic vascular disease. The mechanisms underlying the vasculoprotective effects of a third-generation calcium channel blocker, azelnidipine, are incompletely understood. We asked whether azelnidipine attenuates atherosclerosis in monkeys and mice beyond its blood pressure-lowering effects. Cynomolgus monkeys were randomized to three groups after 4 weeks of a high cholesterol diet: control group (no treatment) and 3 and 10 mg/kg daily azelnidipine; these doses have no effect on systemic arterial pressure or heart rate. Atherosclerosis was induced in the aorta by balloon injury, and the diet and treatment were continued for an additional 24 weeks. Azelnidipine did not affect blood lipid profiles, but reduced the development of atherosclerosis as detected by the elimination of local oxidative stress and reduced expression of monocyte chemoattractant protein-1 and platelet-derived growth factor. Azelnidipine also reduced the proliferation and migration of vascular smooth muscle cells in vitro. In atherosclerotic ApoE-knockout (ApoE-KO) mice fed a high cholesterol diet, azelnidipine but not amlodipine reduced the development of atherosclerosis. Neither drug changed the lipid profiles or systolic blood pressure of the mice. Thus, azelnidipine at clinically relevant doses exhibited anti-atherosclerotic effects in monkeys and mice independent of its blood pressure-lowering effects, suggesting that azelnidipine might be as a "vasculoprotective calcium channel blocker". (C) 2007 Elsevier Ireland Ltd. All rights reserved.