Placental effects and transfer of sildenafil in healthy and preeclamptic conditions

• Published in: EBioMedicine 2019-07, Vol.45, p.447-455
• Main Authors: Hitzerd, Emilie, Broekhuizen, Michelle, Mirabito Colafella, Katrina M., Glisic, Marija, de Vries, René, Koch, Birgit C.P., de Raaf, Michiel A., Merkus, Daphne, Schoenmakers, Sam, Reiss, Irwin K.M., Danser, A.H. Jan, Simons, Sinno H.P.
• Format: Article
• Language: English
• Subjects: Adult; Cyclic GMP - genetics; Cyclic Nucleotide Phosphodiesterases, Type 1 - genetics; Cyclic Nucleotide Phosphodiesterases, Type 5 - genetics; Female; Humans; Nitric oxide; Nitric Oxide - genetics; Nitric Oxide Synthase Type II - genetics; Phosphodiesterase 5 Inhibitors - administration & dosage; Phosphodiesterase 5 Inhibitors - metabolism; Placenta - drug effects; Placenta - pathology; Placenta perfusion; Pre-Eclampsia - drug therapy; Pre-Eclampsia - genetics; Pre-Eclampsia - pathology; Preeclampsia; Pregnancy; Research paper; RNA, Messenger - genetics; Sildenafil; Sildenafil Citrate - administration & dosage; Sildenafil Citrate - metabolism; Vasodilation - drug effects; Vasoreactivity; Vinca Alkaloids - administration & dosage; Vinca Alkaloids - metabolism
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2019.06.007

The phosphodiesterase-5 inhibitor (PDE5) sildenafil has emerged as a promising treatment for preeclampsia (PE). However, a sildenafil trial was recently halted due to lack of effect and increased neonatal morbidity. Ex vivo dual-sided perfusion of an isolated cotyledon and wire-myography on chorionic plate arteries were performed to study the effects of sildenafil and the non-selective PDE inhibitor vinpocetine on the response to the NO donor sodium nitroprusside (SNP) under healthy and PE conditions. Ex vivo perfusion was also used to study placental transfer of sildenafil in 6 healthy and 2 PE placentas. Furthermore, placental mRNA and protein levels of eNOS, iNOS, PDE5 and PDE1 were quantified. Sildenafil and vinpocetine significantly enhanced SNP responses in chorionic plate arteries of healthy, but not PE placentas. Only sildenafil acutely decreased baseline tension in arteries of both healthy and PE placentas. At steady state, the foetal-to-maternal transfer ratio of sildenafil was 0·37 ± 0·03 in healthy placentas versus 0·66 and 0·47 in the 2 PE placentas. mRNA and protein levels of PDE5, eNOS and iNOS were comparable in both groups, while PDE1 levels were lower in PE. The absence of sildenafil-induced NO potentiation in arteries of PE placentas, combined with the non-PDE-mediated effects of sildenafil and the lack of PDE5 upregulation in PE, argue against sildenafil as the preferred drug of use in PE. Moreover, increased placental transfer of sildenafil in PE might underlie the neonatal morbidity in the STRIDER trial. This study was funded by an mRACE Erasmus MC grant.