17β-雌二醇对蛛网膜下腔出血脑血管痉挛的疗效与其可能机制

性别的差异是否影响颅内动脉瘤破裂所引发蛛网膜下腔出血后的预后，仍未有定论，雌性素对于血管扩张的可能作用也尚未确定。本研究评估17β-雌二醇（estradiol，E2）在大鼠两次出血的蛛网膜下腔出血动物模型中，对于蛛网膜下腔出血引发的脑血管痉挛的治疗效果与可能机制。方法 以0.3 mg/ml E2混合玉米油填充于30 mm长的硅胶管（Silastic tube），于雄性大鼠引发蛛网膜下腔出血后1 h，包埋于动物皮下。测量包埋的第0、1、2、3、4及7天大鼠血中E2浓度。脑血管痉挛的程度以第一次出血后7天的基底动脉横切面平均面积来评估。同时检查基底动脉内皮型一氧化氮合酶（endothelial nitric oxide synthase，eNOS）及诱导型一氧化氮合酶（Inducible nitric oxide synthase，iNOS）的表现。结果 以E2治疗大鼠的血中浓度维持在生理浓度（56～92 pg/ml），与给予赋形药物的溶剂对照组相比较，研究组E2浓度的增加有统计学上的意义。E2治疗能有意义的减少蛛网膜下腔出血引发的脑血管痉挛（P <0.01）。E2治疗能有意义的减少脑血管痉挛后基底动脉iNOS-mRNA及蛋白质的表达增加，而对照组无此作用。脑血管痉挛后eNOS-mRNA及蛋白质的表达受压抑，但可经E2治疗而减缓。结论 建议持续性给予E2，维持其于生理浓度，可防止蛛网膜下腔出血后的脑血管痉挛，E2防止蛛网膜下腔出血后脑血管痉挛的效益，部分与E2可防止蛛网膜下腔出血后iNOS的表达及保留eNOS的表达有关。因此，E2对于治疗蛛网膜下腔出血后的脑血管痉挛是一种值得进一步探讨的方法。

Effects of 17beta-estradiol in Attenuating Experimental Subarachnoid Hemorrhage-Induced Cerebral Vasospasm

Objective Although cerebral vasospasm after aneurismal subarachnoid hemorrhage （SAH） has been recognized for over half of a century, it remains a major complication in patients suffering from SAH. As the problem of no effective treatment for cerebral vasospasm still exists, the pathophysiological mechanism contributing to arterial dysfunction needs intensive study. The present study evaluates the effect and possible mechanism of 17β-estradiol （E2） on SAH-induced vasospasm in a two-hemorrhage rodent model of SAH.
Methods A 30-mm Silastic tube filled with E2 in corn oil （0.3 mg/ml） was subcutaneously implanted in male rats. Serum levels of E2 were measured on day 0, 1, 2, 3, 4, and 7 after implantation. The degree of vasospasm was determined by averaging the cross sectional areas of the basilar artery 7 days after the first SAH. Expressions of endothelial nitric oxide synthase （eNOS） and inducible nitric oxide synthase （iNOS） in basilar artery were also evaluated.
Results Serum levels of E2 in the E2-treated rats were at physiological levels （56-92 pg/ml） and were significantly higher than those in the control and vehicle groups. E2-treatment significantly （P〈0.01） attenuated SAH-induced vasospasm. Induction of iNOS-mRNA and protein in basilar artery by SAH was significantly diminished by E2-treatment but not by vehicle. The SAH-induced suppression of eNOS-mRNA and protein was relieved by E2 treatment. Conclusion These results suggest that continuous treatment of E2 at physiological level prevents cerebral vasospasm following SAH. The beneficial effect of E2 may be, in part, related to prevent the augmentation of iNOS expression and preserve the normal eNOS expression after SAH. E2- treatment holds therapeutic promise in the treatment of cerebral vasospasm following SAH and is meritorious of further investigation.