Gillis Ellen E, Mooney Jennifer N, Garrett Michael R, Granger Joey P, Sasser Jennifer M
From the Departments of Pharmacology and Toxicology (E.E.G., J.N.M., M.R.G., J.M.S.), Medicine (M.R.G.), and Physiology and Biophysics (J.P.G.), University of Mississippi Medical Center, Jackson.
Hypertension. 2016 Mar;67(3):647-53. doi: 10.1161/HYPERTENSIONAHA.115.06071. Epub 2016 Jan 4.
Preeclampsia, a hypertensive disorder of pregnancy, is detrimental to both mother and fetus. There is currently no effective treatment, but sildenafil, a phosphodiesterase-5 inhibitor, has been proposed as a potential therapy to reduce blood pressure and improve uteroplacental perfusion in preeclamptic patients. We hypothesized that sildenafil would improve the maternal syndrome and fetal outcomes in the Dahl S rat model of superimposed preeclampsia. Dahl S rats were mated, and half received sildenafil (50 mg/kg per day, via food) from day 10 through day 20 of pregnancy. The untreated Dahl S rats had a significant rise in blood pressure and a 2-fold increase in urinary protein excretion from baseline to late pregnancy; however, sildenafil-treated Dahl S rats exhibited ≈40 mm Hg drops in blood pressure with no rise in protein excretion. Sildenafil also increased creatinine clearance and reduced nephrinuria and glomerulomegaly. Sildenafil treatment reduced the uterine artery resistance index during late pregnancy in the Dahl S rat and improved fetal outcomes (survival, weight, and litter size). In addition, 19% of all pups were resorbed in untreated rats, with no incidence of resorptions observed in the treated group. Furthermore, tumor necrosis factor-α, endothelin-1, and oxidative stress, which are characteristically increased in women with preeclampsia and in experimental models of the disease, were reduced in treated rats. These data suggest that sildenafil improves the maternal syndrome of preeclampsia and blood flow to the fetoplacental unit, providing preclinical evidence to support the hypothesis that phosphodiesterase type 5 inhibition may be an important therapeutic target for the treatment of preeclampsia.
子痫前期是一种妊娠期高血压疾病，对母亲和胎儿都有损害。目前尚无有效治疗方法，但磷酸二酯酶-5抑制剂西地那非已被提议作为一种潜在疗法，用于降低子痫前期患者的血压并改善子宫胎盘灌注。我们假设西地那非可改善叠加子痫前期的Dahl S大鼠模型中的母体综合征和胎儿结局。将Dahl S大鼠进行交配，其中一半从妊娠第10天至第20天通过食物给予西地那非（50 mg/kg/天）。未治疗的Dahl S大鼠血压从基线到妊娠晚期显著升高，尿蛋白排泄增加2倍；然而，接受西地那非治疗的Dahl S大鼠血压下降约40 mmHg，且蛋白排泄未增加。西地那非还增加了肌酐清除率，减少了肾蛋白尿和肾小球肿大。西地那非治疗降低了Dahl S大鼠妊娠晚期的子宫动脉阻力指数，并改善了胎儿结局（存活率、体重和窝仔数）。此外，未治疗大鼠中19%的幼崽被吸收，而治疗组未观察到吸收现象。此外，子痫前期女性及该疾病实验模型中典型升高的肿瘤坏死因子-α、内皮素-1和氧化应激在治疗大鼠中有所降低。这些数据表明，西地那非改善了子痫前期的母体综合征和胎盘-胎儿单位的血流，为支持5型磷酸二酯酶抑制可能是治疗子痫前期的重要治疗靶点这一假说提供了临床前证据。
