Taguchi J, Abe J, Ohno M, Schwartz S M, Kurokawa K
First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Blood Press Suppl. 1994;5:38-42.
Angiotensin II plays an important role in neointima formation after vascular injury. A rat model of carotid artery injury was used i) to investigate the effect of single topical application of angiotensin II subtype 1 (AT1) receptor antagonists (CV11974, DuP753) in suppressing medial proliferation at day 2 and neointimal proliferation at day 14, and ii) to investigate the antiproliferative effects of additional application of L-arginine (a nitric oxide precursor). Drugs mixed in 25% (W/W) solutions of F127 pluronic gel were applied topically to injured vessels. Early medial proliferation of smooth muscle cells, assessed by the S-bromo-2'-deoxyuridine labelling index, was significantly suppressed by application of CV11974 (5 mg/kg), 7.5% +/- 2.2% vs. 19% +/- 3.9% in the control group. The intima/media ratio following CV11974 (10 mg/kg) or DuP753 (12.5 mg/kg) at day 14 was significantly lower than that in the control group (42% +/- 7%, 43% +/- 14%, and 123% +/- 11%, respectively). Additional application of L-arginine seemed to increase effectiveness, but was not statistically significant. In conclusion, single topical application of AT1 receptor antagonists was effective in suppressing early medial proliferation and neointima formation after balloon injury, suggesting that they may be clinically useful after angioplasty or vascular surgery.
血管紧张素II在血管损伤后的新生内膜形成过程中发挥着重要作用。本研究采用大鼠颈动脉损伤模型，一是为了研究单次局部应用血管紧张素II 1型（AT1）受体拮抗剂（CV11974、DuP753）在第2天抑制中膜增殖以及在第14天抑制新生内膜增殖的效果；二是为了研究额外应用L-精氨酸（一种一氧化氮前体）的抗增殖作用。将药物混入25%（W/W）的F127普朗尼克凝胶溶液中，局部应用于损伤血管。通过5-溴-2'-脱氧尿苷标记指数评估平滑肌细胞的早期中膜增殖情况，应用CV11974（5mg/kg）后，该指标显著受到抑制，CV11974组为7.5%±2.2%，而对照组为19%±3.9%。在第14天，CV11974（10mg/kg）或DuP753（12.5mg/kg）处理后的内膜/中膜比值显著低于对照组（分别为42%±7%、43%±14%和123%±11%）。额外应用L-精氨酸似乎可增强效果，但差异无统计学意义。总之，单次局部应用AT1受体拮抗剂可有效抑制球囊损伤后的早期中膜增殖和新生内膜形成，提示其在血管成形术或血管手术后可能具有临床应用价值。
