川芎嗪合并硫酸镁治疗妊高征大鼠的疗效及机制探讨

EVALUATION OF THE EFFICACY OF LIGUSTRAZINE COLLABORATED WITH MAGNESIUM SULFATE IN THE TREATMENT OF PREGNANCY-INDUCED HYPERTENSION IN RATS

为探讨川芎嗪合并硫酸镁治疗妊高征模型大鼠的疗效及其机制,应用L-NAME7mg/kg/天尾静脉注射,连续4天,建立大鼠妊高征模型,采用川芎嗪合并硫酸镁(川+硫)治疗,连续3天。通过套尾法血压测量和24h尿蛋白测定,观察妊高征孕鼠分组治疗后的各组孕鼠血压、尿蛋白变化。并作新生鼠身长、体重和胎盘重量测定,光镜和透射电镜观察肝、肾和胎盘组织病理学及超微结构变化。结果显示,妊娠晚期给予L-NAME,可导致孕鼠血压升高,尿蛋白增加,幼鼠死胎及畸形发生率增加;单用硫酸镁、川芎嗪或两药合用后孕鼠血压、尿蛋白均显著降低(p<0.01,p<0.001),而(川+硫)组较另两组降低更显著(p<0.01,p<0.001);川芎嗪及(川+硫)治疗后能增加新生鼠身长、提高胎仔体重及胎盘重量(p<0.01);且后者尚能减少胎仔后肢短缩畸形率(p<0.001)。妊高征孕鼠肝细胞有散在的坏死灶;肾小球基底膜广泛增厚、肾小球血管内皮肿胀,肾小管上皮广泛水肿;胎盘蜕膜带、基带均增厚,滋养细胞表面的微绒毛减少;川芎嗪尤其(川+硫)治疗后肝细胞未见坏死灶,肾小球基底膜增厚减少;而且后者肾小球血管内皮形态基本正常,肾小管上皮细胞胞浆水肿减轻;胎盘病变明显减轻。上述结果表明,(川+硫)治疗妊高征孕鼠,效果优于单用硫酸镁或川芎嗪。妊高征孕鼠胎盘存在缺血、缺氧的病理改变;川芎嗪治疗组尤其(川+硫)治疗后肝、肾和胎盘病变明显减轻。

The aim of this study was to evaluate the outcome of treatment of pregnancy——induced hy- pertension (PIH) in rats by Ligustrazine collaborated with magnesium sulfate. PIH rat models were induced with Nω-nitro-L-arginine methyl ester (L-NAME)infusing at 7 mg/kg per day via caudal vein for four days, then treated with Ligustrazine, magnesium sulfate, or both for three days. Rat blood pressure level was measured by the tail-cuff method, 24 hours urine protein was also assayed. The blood pressure and urine proteins of grouped PIH rats were recorded before the start and after the termination of therapy. The body length and the weight of fetal rats, the weight of placentals from pregnant rats were measured. The pla- cental tissues, livers, kidneys of rats were investigated with integrated methods such as histopathologic ob- servation with light microscopy, ultrastructural observation with transmission electron microscopy. L-NAME administration in pregnancy rats during the late pregnancy period had resulted in an rise of blood pres- sure, an increasing of urine protein, death rate of rat fetus, incidence of teratogenesis, and so on. Three groups of PIH rats treated with single magnesium sulfate, Ligustrazine, or Ligustrazine combined with mag- nesium sulfate showed an obvious dropping of the proteinuria, decompression of blood pressure (p<0.01, p<0.001), especially the treatment efficacy in the group of Ligustrazine combined with magnesium sulfate was more significant effective than other two groups(p<0.01, p<0.001). The treatment with both Ligustrazine and magnesium sulfate could increase the body length of newly born rats, the body weight of tomites and the placental weight, furthermore, reduce the rate of the teratosis of hindlimb-shortness (p<0.001). There were diffuse focal necrosis areas in the livers of PIH rats, their glomerular basement membrane had thickened extensively, the glomerular endothelium had swelled, extensive edema in the epithelia of renal tubule was demonstrated. The decidua and basal zone of the placentae of PIH rats all thickened, the mi- crovilli of trophoblasts decreased. After treatment with ligustrazine especially with both Ligustrazine and magnesium sulfate, the necrosis of hepatocytes disappeared. The thickening of glomerular basement mem- brane in the group of ligustrazine or both Ligustrazine and magnesium sulfate treatment reduced; Moreover in the latter group the morphology of glomerular endothelium essentially recovered, the edema in cytoplasms of renal tubular epithelium reduced. The placental lesions were also relieved. The present results indicated the therapeutic effect by Ligustrazine collaborated with magnesium sulfate was better than a single use of Ligustrazine or magnesium sulfate. There were pathological alteration involved ischemia and anoxic in the placental tissues of PIH rats, resembled the placental pathological alteration of the human cases with PIH. The treatment with ligustrazine, and especially both Ligustrazine and magnesium sulfate in PIH rats could obviously relieve the lesions in lives, kidneys and placentae.