Takayama Makoto, Yao Kozo, Wada Michihito
Pharmaceutical Research Center, Kyowa Hakko Kirin Co, Ltd, Sunto-gun, Shizuoka-ken, Japan.
J Biomed Sci. 2009 Jun 26;16(1):57. doi: 10.1186/1423-0127-16-57.
Lysophosphatidylcholine (LPC), an atherogenic component of oxidized low-density lipoprotein, has been shown to induce the attenuation of endothelium-dependent vascular relaxation. Although benidipine, a dihydropyridine-calcium channel blocker, is known to have endothelial protective effects, the effects of benidipine on LPC-induced endothelial dysfunction remain unknown. We examined the effects of benidipine on the impairment of endothelium-dependent relaxation induced by LPC.
Benidipine was administered orally to rats and aortas were then isolated. Aortic rings were treated with LPC and endothelial functions were then evaluated. Additionally, the effects of benidipine on intracellular calcium concentration ([Ca2+]i) and membrane fluidity altered by LPC in primary cultured rat aortic endothelial cells were examined. [Ca2+]i was measured using the fluorescent calcium indicator fura-2. Membrane fluidity was monitored by measuring fluorescence recovery after photobleaching.
Treatment with LPC impaired endothelial function. Benidipine prevents the impairment of relaxation induced by LPC. Acetylcholine elicited an increase in [Ca2+]i in fura-2 loaded endothelial cells. The increase in [Ca2+]i was suppressed after exposure to LPC. Plasma membrane fluidity increased following incubation with LPC. Benidipine inhibited the LPC-induced increase in membrane fluidity and impairment of increase in [Ca2+]i.
These results suggest that benidipine inhibited LPC-induced endothelial dysfunction by maintaining increase in [Ca2+]i. Benidipine possesses membrane stabilization properties in LPC-treated endothelial cells. It is speculated that the preservation of membrane fluidity by benidipine may play a role in the retainment of calcium mobilization. The present findings may provide new insights into the endothelial protective effects of benidipine.
溶血磷脂酰胆碱（LPC）是氧化型低密度脂蛋白的致动脉粥样硬化成分，已被证明可诱导内皮依赖性血管舒张功能减弱。尽管二氢吡啶类钙通道阻滞剂贝尼地平已知具有内皮保护作用，但其对LPC诱导的内皮功能障碍的影响仍不清楚。我们研究了贝尼地平对LPC诱导的内皮依赖性舒张功能损害的影响。
给大鼠口服贝尼地平，然后分离主动脉。用LPC处理主动脉环，然后评估内皮功能。此外，研究了贝尼地平对原代培养的大鼠主动脉内皮细胞中LPC改变的细胞内钙浓度（[Ca2+]i）和膜流动性的影响。使用荧光钙指示剂fura-2测量[Ca2+]i。通过测量光漂白后的荧光恢复来监测膜流动性。
LPC处理损害了内皮功能。贝尼地平可预防LPC诱导的舒张功能损害。乙酰胆碱使加载fura-2的内皮细胞中的[Ca2+]i增加。暴露于LPC后，[Ca2+]i的增加受到抑制。与LPC孵育后，质膜流动性增加。贝尼地平抑制LPC诱导的膜流动性增加和[Ca2+]i增加的损害。
这些结果表明，贝尼地平通过维持[Ca2+]i的增加来抑制LPC诱导的内皮功能障碍。贝尼地平在LPC处理的内皮细胞中具有膜稳定特性。推测贝尼地平对膜流动性的维持可能在钙动员的保留中起作用。本研究结果可能为贝尼地平的内皮保护作用提供新的见解。
