Mueck A O, Seeger H, Deuringer F U, Wallwiener D
Department of Obstetrics and Gynecology, University of Tuebingen, Germany.
Menopause. 2001 May-Jun;8(3):216-21. doi: 10.1097/00042192-200105000-00012.
The combination of an estrogen with a statin for therapy of postmenopausal women is of interest because both substance classes exert beneficial effects on the lipid profile. However, both substance classes also elicit positive direct effects on the vasculature. Therefore in the present in vitro study an estrogen/statin combination was investigated for its effect on biochemical markers of endothelial function.
In endothelial cell cultures from human coronary arteries, the effect of estradiol/fluvastatin, alone and in equimolar combinations, were tested at the concentrations 0.01, 0.1, and 1 microM. The vasodilator prostacyclin, the vasoconstrictor endothelin, endothelial nitric oxide synthase (responsible for synthesis of the vasodilator nitric oxide), the procoagulatory factor plasminogen activator inhibitor-1, and the monocyte chemoattractant protein were chosen as markers.
The estradiol/fluvastatin combination was able to increase prostacyclin production (25-100%) in an additive manner. The reduction of endothelin synthesis in the range of 21-46% was higher with the combination than with the monosubstances; the reduction, however, was not statistically significant. The expression of endothelial nitric oxide synthase was not significantly increased by the combination compared with the monosubstances, however, a tendency to an additive increase was observed. For the synthesis of plasminogen activator inhibitor-1, no significant changes were seen for either the monosubstances or the combination. The synthesis of monocyte chemoattractant protein-1 was decreased by the combination between 21% and 40%; the decrease, however, was not statistically significant compared with the effect of the monosubstances. The effective estradiol concentrations are higher than can be achieved by replacement therapy; in contrast, fluvastatin was effective at concentrations that can be reached during clinical treatment.
These results indicate that an estrogen/statin combination exerts beneficial effects on the vasculature that seem to be superior to the effects of the monosubstances. The changes found for the biochemical markers can improve endothelial function. The presented results should encourage the performance of clinical studies in cardiovascular risk patients with estrogen/statin combinations.
雌激素与他汀类药物联合用于治疗绝经后女性备受关注，因为这两类药物对血脂谱均有有益作用。然而，这两类药物对血管系统也有直接的积极影响。因此，在本项体外研究中，对雌激素/他汀类药物组合对内皮功能生化标志物的影响进行了研究。
在人冠状动脉内皮细胞培养物中，测试了雌二醇/氟伐他汀单独使用及等摩尔组合在0.01、0.1和1微摩尔浓度下的作用。选择血管舒张剂前列环素、血管收缩剂内皮素、负责合成血管舒张剂一氧化氮的内皮型一氧化氮合酶、促凝血因子纤溶酶原激活物抑制剂-1和单核细胞趋化蛋白作为标志物。
雌二醇/氟伐他汀组合能够以相加的方式增加前列环素的生成（25%-100%）。组合用药时内皮素合成的降低幅度（21%-46%）高于单一药物，但降低幅度无统计学意义。与单一药物相比，组合用药并未显著增加内皮型一氧化氮合酶的表达，不过观察到有相加增加的趋势。对于纤溶酶原激活物抑制剂-1的合成，单一药物及组合用药均未见显著变化。组合用药使单核细胞趋化蛋白-1的合成降低了21%-40%；但与单一药物的作用相比，降低幅度无统计学意义。有效的雌二醇浓度高于替代疗法所能达到的浓度；相比之下，氟伐他汀在临床治疗期间所能达到的浓度下即有效。
这些结果表明，雌激素/他汀类药物组合对血管系统具有有益作用，似乎优于单一药物的作用。所发现的生化标志物变化可改善内皮功能。本研究结果应促使开展针对心血管风险患者的雌激素/他汀类药物组合的临床研究。
