多沙唑嗪光学异构体对大鼠主动脉平滑肌细胞增殖的选择性抑制作用

目的观察多沙唑嗪(racemic-doxazosin,rac-DOX)及其对映体(S-DOX、R-DOX)对大鼠血管平滑肌细胞(vascularsmooth muscle cells,VSMCs)增殖的影响。方法采用培养的大鼠主动脉血管平滑肌细胞,应用MTT比色法,测定VSMCs的增殖活力,Giemsa’s染色观察VSMCs的形态学改变。结果在3~30μmol.L-1浓度范围,S-DOX、R-DOX和rac-DOX作用于VSMCs 96 h,均抑制大鼠胸主动脉VSMCs增殖活动;但是,S-DOX的抑制作用强于同浓度R-DOX(P<0.05),与同浓度rac-DOX的抑制作用无差别。以30μmol.L-1浓度的药物处理VSMCs 48 h、72 h和96 h;S-DOX对主动脉VSMCs增殖的抑制率依次为28.67%、34.51%和56.89%,R-DOX为22.59%、26.66%和45.79%,rac-DOX为21.88%、32.84%和52.04%。以不同浓度的药物处理大鼠胸主动脉VSMCs 96 h,rac-DOX、S-DOX和R-DOX抑制VSMCs增殖达40%的浓度(IC40)分别为(12.1±2.6)、(10.2±1.3)和(20.9±2.2)μmol.L-1;R-DOX的IC40值大于rac-DOX和S-DOX(P<0.01)。S-DOX处理后,VSMCs出现细胞体积变小,核固缩,核边集等形态学改变。结论S-DOX和R-DOX对大鼠胸主动脉VSMCs的抗增殖作用具有化学结构的立体选择性,S-DOX的抗VSMCs增殖作用明显强于R-DOX。

Chiral selective effects of doxazosin and its enantiomers on cell proliferation in cultured vascular smooth muscle cells of the rat aorta

Aim To investigate the effect of racemic-doxazosin(rac-DOX),S-doxazosin(S-DOX) and R-doxazosin(R-DOX) on the proliferation of vascular smooth muscle cells(VSMCs) of the rat aorta.Methods VSMCs of the rat aorta were cultured,MTT assay was used to determine the cell proliferation and the morphological changes in VSMCs were analyzed using Giemsa's staining.Results The treatment with rac-DOX,S-DOX or R-DOX at 3~30 μmol·L-1 for 96 h inhibited the proliferation of VSMCs significantly.However,the inhibitory effect of S-DOX on cell proliferation was more potent than that of R-DOX at the same concentration(P<0.05).When the VSMCs were exposed to rac-DOX,S-DOX and R-DOX at 30 μmol·L-1 for 48 h,72 h and 96 h,the inhibition rate of VSMCs proliferation by the three agents was 21.88%,32.84% and 52.04%(rac-DOX);28.67%,34.51% and 56.89%(S-DOX);and 22.59%,26.66% and 45.79%(RDOX),respectively.When the VSMCs were exposed to rac-DOX,S-DOX and R-DOX at different concentrations for 96 h,the concentration required for 40percent inhibition(IC40) of the VSMCs proliferation was 12.1±2.6(rac-DOX),10.2±1.3(S-DOX) and 20.9±2.2(R-DOX,μmol·L-1),respectively.The IC40 of R-DOX was significantly higher than that of rac-DOX and S-DOX(P<0.01).Morphological changes in VSMCs induced by S-DOX treatment included cell shrinkage,chromatin condensation and chromatin margination.Conclusions S-DOX and R-DOX have chiral selective effects on cell proliferation in cultured VSMCs of the rat aorta,and the inhibition on cell proliferation of S-DOX was significantly stronger than that of R-DOX.