Evaluation of Sildenafil and Tadalafil for Reversing Constriction of Fetal Arteries in a Human Placenta Perfusion Model

被引:26
作者
Walton, Robert B. [1 ]
Reed, Luckey C. [1 ]
Estrada, Sarah M. [1 ]
Schmiedecke, Stacey S. [1 ]
Villazana-Kretzer, Diana L. [1 ]
Napolitano, Peter G. [1 ]
Ieronimakis, Nicholas [2 ]
机构
[1] Madigan Army Med Ctr, Dept Obstet & Gynecol, Joint Base Lewis McCord, Tacoma, WA 98431 USA
[2] Madigan Army Med Ctr, Joint Base Lewis McCord, Dept Clin Invest, 9040 Jackson Ave, Tacoma, WA 98431 USA
关键词
arterial pressure; gestational age; sildenafil; tadalafil; vasodilation; INTRAUTERINE GROWTH RESTRICTION; LOW-DOSE ASPIRIN; ANGIOTENSIN-II; CHORIONIC ARTERIES; CITRATE TREATMENT; L-ARGININE; PREGNANCY; PHARMACOKINETICS; COTYLEDON; PREECLAMPSIA;
D O I
10.1161/HYPERTENSIONAHA.117.10738
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
Fetal growth restriction resulting from reduced placental blood perfusion is a major cause of neonatal morbidity and mortality. Aside from intense surveillance and early delivery, there is no treatment for fetal growth restriction. A potential treatment associated with placental vasoconstriction is the class of PDE5 (phosphodiesterase type 5) inhibitors such as sildenafil, which is known to cross the placenta. In contrast, tadalafil, a more potent and selective PDE5 inhibitor has not been studied in pregnancy or experimental models of fetal growth restriction. Therefore, we compared the efficacy of these 2 PDE5 inhibitors for reversing vasoconstriction in an ex vivo human placental model and evaluating molecular and physiological responses. Sildenafil and tadalafil were infused into the intervillous space in a preconstricted human placental dual cotyledon, dual perfusion assay for the comparison of arteriole pressures and molecular indicators of drug inhibition. Results indicate a decrease arterial pressure with sildenafil citrate compared with controls, whereas tadalafil showed no difference. PDE5 and endothelial nitric oxide synthase activity were altered with sildenafil but not tadalafil. Sildenafil citrate improved preconstricted placental arterial perfusion in a human placental model, whereas tadalafil showed no response. It is possible that tadalafil did not cross the human placental barrier or was degraded by trophoblasts. This study supports human clinical trials exploring sildenafil as a potential treatment for improving fetal blood flow in fetal growth restriction associated with vasoconstriction.
引用
收藏
页码:167 / 176
页数:10
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