艾力沙坦酯对SD大鼠围产期毒性的试验研究

Perinatal toxicity of allisartan isoproxil in SD rats

目的:观察血管紧张素Ⅱ受体拮抗剂艾力沙坦酯(allisartan isoproxil,ALS-3)对孕期、哺乳期的SD大鼠及子代生长发育和生殖功能的影响。方法:实验设4组,即ALS-3高(270 mg/kg)、中(90 mg/kg)、低(30 mg/kg)剂量组和溶媒对照组(0.5%羧甲基纤维素钠),孕鼠于胚胎着床到幼仔离乳期间灌胃给药,每日1次,对母代(F0)的生殖能力和子代(F1、F2)的生长发育能力进行观察结果:实验中有1只孕鼠(270 mg/kg组)因难产而死亡,其余未见明显异常情况;F0母鼠于分娩后21 d处死并解剖,各组动物均未见异常。而270 mg/kg剂量组仔鼠(F1)出生后第7天(D7)、D21(雌性和雄性)体质量均低于溶媒对照组,差异有统计学意义(P<0.05);F1其他日龄仔鼠及F2各剂量组仔鼠体质量与溶媒对照组相比,差异均无统计学意义(P>0.05);270mg/kg剂量组仔鼠(F1)的哺育死亡率高于溶媒对照组(P<0.05),90mg/kg剂量组仔鼠(F2)与溶媒对照组相比,哺育死亡率偏低(P<0.01),其他指标与溶媒对照组相比,差异无统计学意义(P>0.05)。结论:艾力沙坦酯30～270mg/kg灌胃对子代大鼠(F1和F2)的生理发育、行为、F1代性成熟及生殖功能均未发现明显毒性作用,但270 mg/kg剂量组对妊娠雌性大鼠(F0)的哺乳功能和仔鼠(F1)离乳前的生长发育有毒性或干扰作用。

OBJECTIVE：To observe the toxic effects of allisartan isoproxil（ALS-3） on maternal SpragueDawley （SD） rats during pregnancy,lactation period,the growth and development,and the reproduction of their offsprings.METHODS：ALS-3 was administered by intragastric method at a dose level of 0（control）,30,90 or 270 mg/kg from day 15 of gestation to day 21 after parturition to examine the effects of ALS-3 on the reproductive capacity in the maternal rats and the growth and development of the offsprings.RESULTS：A pregnant rat（270 mg/kg） died due to dystocia.No obvious abnormality was observed in other maternal rats（F0） sacrificed 21 days after delivery.The body weight of F1 offspring on PND 7 and PND 21 in the 270 mg/kg group decreased significantly compared with control group （P0.05）,and the body weight of Fl offsprings at other age and F2 offsprings in every test group showed no significant difference with control group（P0.05）.Compared with control group,the breast feeding mortality of Fl offsprings in the 270 mg/kg group was significantly increased,while F2 offsprings in the 90 mg/kg group decreased（P0.01）.Other indexes showed no significant difference compared with control group（P0.05）.CONCLUSION：ALS-3 at 270 mg/kg had obvious toxic effects on lactation of F0 generation and growth or development of F1 offsprings before weaning.However no effects on the functional,behavioral or learning abilities or reproductive performance in offsprings were observed in the 30 and 90 mg/kg groups.