Sildenafil attenuates placental ischemia-induced hypertension
Sildenafil attenuates placental ischemia-induced hypertension
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DOI：
10.1152/ajpregu.00216.2013
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发表时间：
2013-08-01
影响因子：
2.8
通讯作者：
Granger, Joey P.
中科院分区：
文献类型：
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作者：
George, Eric M.;Palei, Ana C.;Granger, Joey P.
先兆子痫是一种妊娠并发症，以高血压、蛋白尿和母体内皮功能障碍为特征。该疾病病因的一个核心因素是胎盘缺氧/缺血，释放致病性可溶性因子。目前子痫前期尚无有效治疗方法，但有人建议使用磷酸二酯酶5（PDE-5）抑制剂西地那非，因为PDE-5在子宫内富集，其拮抗作用可以改善子宫胎盘功能。在这里，我们在子宫灌注压降低（RUPP）大鼠模型中报告，口服西地那非可有效减轻妊娠期间胎盘缺血引起的高血压。与对照动物相比，RUPP 动物的动脉压显着升高（132 +/- 3 vs. 100 +/- 2 mmHg；P < 0.05）。口服西地那非（45 mg.kg(-1).day(-1)）对对照大鼠的血压没有影响，但降低了 RUPP 大鼠的血压（115 +/- 1 mmHg；P < 0.05）。 RUPP 诱导胎盘 sFlt-1 的变化，血管内皮生长因子 (VEGF) 不受西地那非给药的影响，游离血浆 VEGF 的减少也是如此。与对照组相比，RUPP 动物的髓质 PDE-5/β-肌动蛋白比率显着增加（1 +/- 0.14 与 1.63 +/- 0.18；P < 0.05）表达，导致肾髓 cGMP 降低（1.5 +/- 0.15 与 0.99 +/- 0.1 pmol/μ g 蛋白，P < 0.05）。虽然西地那非对对照动物的肾髓质 cGMP 没有影响，但它显着增加了 RUPP 动物的 cGMP（1.3 +/- 0.1 pmol/mu g 蛋白；P < 0.05）。这些数据表明西地那非可能为先兆子痫期间高血压的治疗提供有效的治疗选择。
Preeclampsia is a complication of pregnancy that is marked by hypertension, proteinuria, and maternal endothelial dysfunction. A central factor in the etiology of the disease is the development of placental hypoxia/ischemia, which releases pathogenic soluble factors. There is currently no effective treatment for preeclampsia, but the phosphodiesterase-5 (PDE-5) inhibitor sildenafil has been suggested, as PDE-5 is enriched in the uterus, and its antagonism could improve uteroplacental function. Here, we report in the reduced uterine perfusion pressure (RUPP) rat model that administration of oral sildenafil is effective in attenuating placental ischemia-induced hypertension during gestation. RUPP animals have significantly elevated arterial pressure compared with control animals (132 +/- 3 vs. 100 +/- 2 mmHg; P < 0.05). Administration of oral sildenafil (45 mg.kg(-1).day(-1)) had no effect on blood pressure in control rats but decreased pressure in RUPP rats (115 +/- 1 mmHg; P < 0.05). RUPP induced changes in placental sFlt-1, and vascular endothelial growth factor (VEGF) was unaffected by sildenafil administration, as was the decrease in free plasma VEGF. RUPP animals had a significant increase in medullary PDE-5/beta-actin ratio (1 +/- 0.14 vs. 1.63 +/- 0.18; P < 0.05) expression with a resulting reduction in renal medullary cGMP (1.5 +/- 0.15 vs. 0.99 +/- 0.1 pmol/mu g protein, P < 0.05) compared with controls. Although sildenafil had no effect on renal medullary cGMP in control animals, it significantly increased cGMP in RUPP animals (1.3 +/- 0.1 pmol/mu g protein; P < 0.05). These data suggest that sildenafil might provide an effective therapeutic option for the management of hypertension during preeclampsia.