Selective iNOS inhibitor, ONO1714 successfully retards the development of high-cholesterol diet induced atherosclerosis by novel mechanism
Selective iNOS inhibitor, ONO1714 successfully retards the development of high-cholesterol diet induced atherosclerosis by novel mechanism
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DOI：
10.1016/j.atherosclerosis.2005.10.023
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发表时间：
2006-08-01
期刊：
影响因子：
5.3
通讯作者：
Iguchi, Akihisa
中科院分区：
文献类型：
--
作者：
Hayashi, Toshio;Matsui-Hirai, Hisako;Iguchi, Akihisa
目的：诱导型一氧化氮合酶（iNOS）仅存在于动脉粥样硬化斑块的深部。然而，iNOS在动脉粥样硬化发展中的作用尚不清楚。因此，我们调查的相关性iNOS inhibition.Methods和结果：7组雄性家兔饲喂0.5%的高胆固醇饮食（HCD）8周。Gp 1-HCD仅喂食HCD; Gp 2 -017喂食HCD和ONO 1714（一种iNOS抑制剂）; Gp 3-AG喂食HCD和氨基胍（AG）（一种iNOS抑制剂）; Gp 4-AR喂食HCD和L-精氨酸; Gp 5-AR-O 17喂食HCD和L-精氨酸以及ONO 1714; Gp 6-LNA喂食HCD和L-NAME（NOS抑制剂）; Gp 7-LN-O 17用L-NAME加ONO 1714饲喂HCD。ONO 1714使动脉粥样硬化减少约70%（病变占据的面积：在Gp 2 -017中为3.0 +/-0.4%，在Gp 1-HCD中为10.3 +/-1.6%），并且还减少了Gp 7-LN-017中的动脉粥样硬化。ONO复合物增强了L-精氨酸的抗动脉粥样硬化作用。氨基胍也显示出抗动脉粥样硬化作用。在Gp 2 -017和Gp 5-AR-O 17中，紧张度相关的基础NO释放和乙酰胆碱诱导的NO依赖性舒张得到改善。Gp 2 -017和Gp 7-LN-O 17的O-2（-）释放减少。结论：ONO 1714可延缓家兔动脉粥样硬化的进展。虽然内皮型一氧化氮合酶（eNOS）的上调和O-2（-）的减少可能在这种延迟中起作用，但iNOS的抑制可能是主要因素，单独是不够的。(c)2005爱思唯尔爱尔兰有限公司保留所有权利。
Objective: We have reported that inducible nitric oxide synthase (iNOS) is present only in deep areas of plaque in atherosclerosis. However, the role of iNOS in the development of atherosclerosis is not well known. We therefore investigated the relevance of iNOS inhibition.Methods and results: Seven groups of male rabbits were fed a 0.5% high-cholesterol diet (HCD) for 8 weeks. Gp1-HCD was fed HCD only; Gp2-017 was fed HCD with ONO1714, an iNOS inhibitor; Gp3-AG was fed HCD with amino-guanidine (AG), an iNOS inhibitor; Gp4-AR was fed HCD with L-arginine; Gp5-AR-O17 was fed HCD with L-arginine with ONO 1714; Gp6-LNA was fed HCD with L-NAME (a NOS inhibitor); and Gp7-LN-O17 was fed HCD with L-NAME plus ONO1714. ONO1714 decreased atherosclerosis by about 70% (area occupied by lesions: 3.0 +/- 0.4% in Gp2-017 versus 10.3 +/- 1.6% in Gpl-HCD) and also decreased atherosclerosis in Gp7-LN-O17. The ONO compound enhanced the atheroprotective effect Of L-arginine. Amino-guanidine also showed an anti-atherosclerotic effect. Tone-related basal NO release and acetylcholine-induced NO-dependent relaxation were improved in Gp2-017 and Gp5-AR-O17. O-2(-) release was decreased in Gp2-017 and Gp7-LN-O17.Conclusion: ONO1714 retards the progression of atherosclerosis in rabbits. Although the up-regulation of endothelial nitric oxide synthase (eNOS) and the decrease Of O-2(-) may play roles in this retardation, the inhibition of iNOS may be the principal factor, alone was not sufficient. (c) 2005 Elsevier Ireland Ltd. All rights reserved.