Seki J, Nishio M, Kato Y, Motoyama Y, Yoshida K
Department of Pharmacology, Fujisawa Pharmaceutical Co. Ltd., Osaka, Japan.
Atherosclerosis. 1995 Sep;117(1):97-106. doi: 10.1016/0021-9150(95)05563-c.
The effect of FK409, a new nitric-oxide (NO) donor, on neointimal formation of rat carotid arteries following balloon injury was studied. The intimal thickening at 14 days was strongly suppressed by twice daily administration of FK409 at 10 mg/kg from 2 days before to 13 days after injury. The neointima area and neointima/media ratio were decreased by 48.0% (P < 0.01) and 38.5% (P < 0.01), respectively, compared with control. On the other hand, isosorbide dinitrate (ISDN), a classical nitro-vasodilator, did not suppress intimal thickening even at 100 mg/kg twice a day. An in vivo 5-bromo-2'-dedoxyuridine (BrdU) uptake study revealed that FK409 inhibited the proliferative response of smooth muscle cells (SMC) in media at early stage of injury. In fact, the neointimal formation at 14 days was inhibited by the short term administration of FK409 only from the day of injury to 4 days after at 10 mg/kg twice a day. In cultured rat SMC, FK409 (1-10 mumol/l) markedly enhanced intracellular c-GMP and inhibited the proliferation in 10% FBS-containing medium. These results suggest that FK409 suppresses intimal thickening following balloon injury of the rat carotid artery by inhibition of SMC proliferation.
研究了新型一氧化氮（NO）供体FK409对大鼠颈动脉球囊损伤后新生内膜形成的影响。从损伤前2天至损伤后13天，每天两次给予10mg/kg的FK409，可强烈抑制14天时的内膜增厚。与对照组相比，新生内膜面积和新生内膜/中膜比值分别降低了48.0%（P<0.01）和38.5%（P<0.01）。另一方面，经典的硝基血管扩张剂硝酸异山梨酯（ISDN）即使每天两次给予100mg/kg也不能抑制内膜增厚。一项体内5-溴-2'-脱氧尿苷（BrdU）摄取研究表明，FK409在损伤早期抑制了中膜平滑肌细胞（SMC）的增殖反应。事实上，仅在损伤当天至损伤后4天每天两次给予10mg/kg的FK409短期给药就抑制了14天时的新生内膜形成。在培养的大鼠SMC中，FK409（1-10μmol/L）显著增强细胞内c-GMP，并抑制含10%胎牛血清培养基中的细胞增殖。这些结果表明，FK40抑制大鼠颈动脉球囊损伤后的内膜增厚是通过抑制SMC增殖实现的。
