Wassmann Sven, Laufs Ulrich, Stamenkovic Djordje, Linz Wolfgang, Stasch Johannes-Peter, Ahlbory Katja, Rösen Renate, Böhm Michael, Nickenig Georg
Medizinische Klinik und Poliklinik, Innere Medizin III, Universitätskliniken des Saarlandes, Homburg/Saar, Germany.
Circulation. 2002 Apr 30;105(17):2083-91. doi: 10.1161/01.cir.0000014618.91633.67.
It has not been completely clarified whether selective estrogen receptor modulators (SERMs) such as raloxifene exert vasoprotective effects similar to those of estrogens.
To investigate vascular effects of raloxifene, male spontaneously hypertensive rats were treated for 10 weeks with either raloxifene (10 mg x kg(-1) x d(-1)) or vehicle. Raloxifene improved endothelium-dependent vasodilatation but had no effect on either endothelium-independent vasorelaxation or phenylephrine-induced vasoconstriction. Raloxifene treatment increased the release of NO from the vessel wall by enhanced expression and activity of endothelial NO synthase. Blood pressure reduction after bradykinin infusion was more pronounced in animals treated with SERMs. The production of superoxide in intact aortic segments was decreased by raloxifene treatment. Administration of raloxifene had no effect on the expression of the essential NAD(P)H oxidase subunits p22phox and nox1 in the vasculature but reduced the activity and expression of vascular membrane-bound rac1, a GTPase required for the activation of the NAD(P)H oxidase. Finally, blood pressure levels were significantly decreased in spontaneously hypertensive rats treated with raloxifene. All SERM effects were also detected in healthy age-matched Wistar rats. In cultured rat aortic vascular smooth muscle cells, raloxifene inhibited angiotensin II-induced reactive oxygen species production dependent on estrogen receptor activation.
Raloxifene treatment improves hypertension-induced endothelial dysfunction by increased bioavailability of NO. This is achieved by an increased activity of endothelial NO synthase and by an estrogen receptor-dependent reduction in release of reactive oxygen species from vascular cells. These vascular effects cause a profound blood pressure reduction and lead to decreased vascular damage in male spontaneously hypertensive rats.
雷洛昔芬等选择性雌激素受体调节剂（SERM）是否发挥与雌激素类似的血管保护作用尚未完全明确。
为研究雷洛昔芬的血管效应，对雄性自发性高血压大鼠用雷洛昔芬（10 mg·kg⁻¹·d⁻¹）或赋形剂治疗10周。雷洛昔芬改善了内皮依赖性血管舒张，但对内皮非依赖性血管舒张或去氧肾上腺素诱导的血管收缩均无影响。雷洛昔芬治疗通过增强内皮型一氧化氮合酶的表达和活性增加了血管壁一氧化氮的释放。缓激肽输注后，接受SERM治疗的动物血压降低更为明显。雷洛昔芬治疗降低了完整主动脉段超氧化物的产生。给予雷洛昔芬对血管中必需的NAD（P）H氧化酶亚基p22phox和nox1的表达无影响，但降低了血管膜结合的rac1的活性和表达，rac1是NAD（P）H氧化酶激活所需的一种GTP酶。最后，用雷洛昔芬治疗的自发性高血压大鼠血压水平显著降低。在年龄匹配的健康Wistar大鼠中也检测到了所有SERM的效应。在培养的大鼠主动脉血管平滑肌细胞中，雷洛昔芬抑制了血管紧张素II诱导的依赖雌激素受体激活的活性氧生成。
雷洛昔芬治疗通过增加一氧化氮的生物利用度改善高血压诱导的内皮功能障碍。这是通过增加内皮型一氧化氮合酶的活性以及雌激素受体依赖性减少血管细胞活性氧的释放来实现的。这些血管效应导致显著的血压降低，并减少雄性自发性高血压大鼠的血管损伤。
