Department of Obstetrics and Gynecology, Mie University Graduate School of Medicine, Japan.
Department of Pharmacy, Mie University Hospital, Japan.
Am J Hypertens. 2017 Dec 8;31(1):89-96. doi: 10.1093/ajh/hpx130.
We investigated the efficacy and mechanisms of tadalafil, a selective phosphodiesterase 5 inhibitor, in treating preeclampsia (PE) with fetal growth restriction (FGR) using L-NG-nitroarginine methyl ester (L-NAME)-induced PE with FGR in pregnant mice as our experimental model.
C57BL/6 mice were divided into 2 groups 11 days postcoitum (d.p.c.). A control group of dams (C dam) received 0.5% carboxymethylcellulose (CMC). A L-NAME-treated group received 1 mg/ml L-NAME dissolved in CMC. The L-NAME-treated dams were divided into 2 subgroups 13 d.p.c. One subgroup continued to receive L-NAME (L dams). The other subgroup received L-NAME with 0.08 mg/ml tadalafil suspended in CMC (TL dams). Maternal systolic blood pressure (SBP) and proteinuria were assessed 16 d.p.c. Fetal weight was recorded, and placentas and maternal kidneys were collected 17 d.p.c.
Maternal SBP, proteinuria, and fetal weight were improved for TL dams compared to L dams. The placental concentration of placental growth factor (PlGF) was higher for TL dams than for the C and L dams. The placental maternal blood sinuses of L dams were narrower than those of C dams, but those of TL dams improved to a similar width as C dams. Glomerular oxidative stress was ameliorated in TL dams compared to L dams.
Tadalafil dilates the placental maternal blood sinuses, which leads to increase PlGF production, and contributes to facilitate fetal growth and improve maternal SBP. Moreover, tadalafil ameliorates glomerular damage by reducing oxidative stress. These results suggest that tadalafil is a candidate for treatment of PE with FGR.
我们使用 L-NG-硝基精氨酸甲酯 (L-NAME) 诱导的伴有胎儿生长受限 (FGR) 的子痫前期 (PE) 孕鼠实验模型，研究了选择性磷酸二酯酶 5 抑制剂他达拉非治疗伴有 FGR 的 PE 的疗效和机制。
将 C57BL/6 小鼠分为两组，受精后 11 天 (d.p.c.)。对照组孕鼠 (C 孕鼠) 给予 0.5%羧甲基纤维素 (CMC)。L-NAME 处理组给予 1mg/ml L-NAME 溶解于 CMC。L-NAME 处理的孕鼠在 13 d.p.c. 时分为两组。一组继续给予 L-NAME (L 孕鼠)。另一组给予 L-NAME 加 0.08mg/ml 他达拉非悬浮于 CMC (TL 孕鼠)。16 d.p.c. 时评估母体收缩压 (SBP) 和蛋白尿。17 d.p.c. 时记录胎儿体重，并采集胎盘和母体肾脏。
与 L 孕鼠相比，TL 孕鼠的母体 SBP、蛋白尿和胎儿体重得到改善。TL 孕鼠的胎盘生长因子 (PlGF) 浓度高于 C 孕鼠和 L 孕鼠。L 孕鼠的胎盘母体血窦比 C 孕鼠的狭窄，但 TL 孕鼠的血窦宽度改善至与 C 孕鼠相似。与 L 孕鼠相比，TL 孕鼠的肾小球氧化应激减轻。
他达拉非扩张胎盘母体血窦，导致 PlGF 产生增加，有助于促进胎儿生长并改善母体 SBP。此外，他达拉非通过减少氧化应激改善肾小球损伤。这些结果表明，他达拉非是治疗伴有 FGR 的 PE 的候选药物。
