Ikeda U, Ikeda M, Kano S, Kanbe T, Shimada K
Department of Cardiology, Jichi Medical School, Tochigi, Japan.
Eur J Pharmacol. 1996 Oct 24;314(1-2):197-202. doi: 10.1016/s0014-2999(96)00551-1.
We investigated the effects of cilostazol, a cAMP phosphodiesterase inhibitor, on nitric oxide (NO) synthesis in cultured rat vascular smooth muscle cells. Incubation of the cultures with interleukin-1 beta (10 ng/ml) for 24 h caused a significant increase in the accumulation of nitrite, a stable metabolite of NO. Although cilostazol itself showed no effect on nitrite accumulation, it stimulated interleukin-1 beta-induced nitrite accumulation in a concentration-dependent manner (10(-8)-10(-5) M). This effect of cilostazol was completely abolished in the presence of NG-monomethyl-L-arginine, actinomycin D or dexamethasone. The cilostazol-induced nitrite production was accompanied by increased inducible NO synthase protein expression. In the presence of dibutyryl-cAMP, interleukin-1 beta-induced nitrite accumulation was further increased, but the stimulatory effect of cilostazol on nitrite accumulation was blunted. The effect of cilostazol was also abolished in the presence of Rp-8-bromoadenosine-3',5-cyclic monophosphorothioate, a competitive inhibitor of protein kinase A. Addition of cilostazol to the cultures significantly increased intracellular cAMP levels of vascular smooth muscle cells. These results indicate that cilostazol increases NO synthesis in interleukin-1 beta-stimulated smooth muscle cells, at least partially through a cAMP-dependent pathway.
我们研究了环磷腺苷磷酸二酯酶抑制剂西洛他唑对培养的大鼠血管平滑肌细胞中一氧化氮（NO）合成的影响。用白细胞介素-1β（10 ng/ml）孵育培养物24小时，导致亚硝酸盐（NO的一种稳定代谢产物）的积累显著增加。尽管西洛他唑本身对亚硝酸盐积累无影响，但它以浓度依赖的方式（10^(-8)-10^(-5) M）刺激白细胞介素-1β诱导的亚硝酸盐积累。在存在NG-单甲基-L-精氨酸、放线菌素D或地塞米松的情况下，西洛他唑的这种作用完全被消除。西洛他唑诱导的亚硝酸盐产生伴随着诱导型一氧化氮合酶蛋白表达的增加。在存在二丁酰环磷腺苷的情况下，白细胞介素-1β诱导的亚硝酸盐积累进一步增加，但西洛他唑对亚硝酸盐积累的刺激作用减弱。在存在蛋白激酶A的竞争性抑制剂Rp-8-溴腺苷-3',5-环磷硫代酸酯的情况下，西洛他唑的作用也被消除。向西洛他唑培养物中添加西洛他唑显著增加了血管平滑肌细胞的细胞内环磷腺苷水平。这些结果表明，西洛他唑至少部分通过环磷腺苷依赖的途径增加白细胞介素-1β刺激的平滑肌细胞中的NO合成。
