Hara T, Kusunoki M, Tsutsumi K, Okada K, Sakamoto S, Ohnaka M, Nakamura T, Miyata T, Nakayama K, Fukatsu A, Kato K, Kakumu S, Nakaya Y
The First Department of Internal Medicine, Aichi Medical University, Japan.
Eur J Pharmacol. 1998 May 29;350(1):75-9. doi: 10.1016/s0014-2999(98)00230-1.
Endothelial function is closely related to development of atherosclerosis and is impaired with aging. The novel compound NO-1886, 4-diethoxyphosphorylmethyl-N-(4-bromo-2-cyanophenyl)benzamid e, is a lipoprotein lipase activator and its long term administration protects against the development of experimental atherosclerosis in animals. The aim of this study was to ascertain whether NO-1886 ameliorates the impaired endothelium-dependent relaxation of rat aorta associated with aging. NO-1886 (50 mg/kg p.o.) was administered to 7-month old rats for 3 months. Plasma lipid, glucose and insulin levels in old control rats (10 months of age) were significantly higher than those of young rats (2 months of age). NO- 1886 decreased plasma triglyceride levels (old rats, 233+/-10 mg/dl; old rats + NO-1886, 172+/-16 mg/dl, P < 0.01) and increased plasma high density lipoprotein (HDL) cholesterol level (old rats, 72+/-6 mg/dl; old rats + NO-1886, 142+/-6 mg/dl, P < 0.001) in old rats, but had no effects on plasma glucose or insulin. The endothelium-dependent relaxation of the thoracic aorta caused by histamine was significantly impaired in old rats (% relaxation at 10(-5.5) M histamine: young rats 25.4+/-3.1%; old rats 14.1+/-1.9%, P < 0.01), an effect completely prevented by NO-1886 (old rats + NO-1886; 22.8+/-2.8%, P < 0.05 vs. old rats). In contrast, NO-1886 showed no effect on the endothelium-independent relaxation by sodium nitroprusside. These results indicate that NO-1886 improves impaired endothelium-dependent relaxation of rat aorta associated with aging, possibly by correcting lipid metabolism.
内皮功能与动脉粥样硬化的发展密切相关，且会随着衰老而受损。新型化合物NO-1886，即4-二乙氧基磷酰甲基-N-(4-溴-2-氰基苯基)苯甲酰胺，是一种脂蛋白脂肪酶激活剂，长期给药可保护动物免受实验性动脉粥样硬化的发展。本研究的目的是确定NO-1886是否能改善与衰老相关的大鼠主动脉内皮依赖性舒张功能受损。将NO-1886（50mg/kg口服）给予7月龄大鼠，持续3个月。老年对照大鼠（10月龄）的血浆脂质、葡萄糖和胰岛素水平显著高于年轻大鼠（2月龄）。NO-1886可降低老年大鼠的血浆甘油三酯水平（老年大鼠，233±10mg/dl；老年大鼠+NO-1886，172±16mg/dl，P<0.01），并提高老年大鼠的血浆高密度脂蛋白（HDL）胆固醇水平（老年大鼠，72±6mg/dl；老年大鼠+NO-1886，142±6mg/dl，P<0.001），但对血浆葡萄糖或胰岛素无影响。组胺引起的胸主动脉内皮依赖性舒张在老年大鼠中显著受损（10^(-5.5)M组胺时的舒张百分比：年轻大鼠25.4±3.1%；老年大鼠14.1±1.9%，P<0.01），NO-1886可完全阻止这种作用（老年大鼠+NO-1886；22.8±2.8%，与老年大鼠相比，P<0.05）。相比之下，NO-1886对硝普钠引起的非内皮依赖性舒张无影响。这些结果表明，NO-1886可能通过纠正脂质代谢来改善与衰老相关的大鼠主动脉内皮依赖性舒张功能受损。
