Placental effects and transfer of sildenafil in healthy and preeclamptic conditions.
Adult
Cyclic GMP
/ genetics
Cyclic Nucleotide Phosphodiesterases, Type 1
/ genetics
Cyclic Nucleotide Phosphodiesterases, Type 5
/ genetics
Female
Humans
Nitric Oxide
/ genetics
Nitric Oxide Synthase Type II
/ genetics
Phosphodiesterase 5 Inhibitors
/ administration & dosage
Placenta
/ drug effects
Pre-Eclampsia
/ drug therapy
Pregnancy
RNA, Messenger
/ genetics
Sildenafil Citrate
/ administration & dosage
Vasodilation
/ drug effects
Vinca Alkaloids
/ administration & dosage
Nitric oxide
Placenta perfusion
Preeclampsia
Sildenafil
Vasoreactivity
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Jul 2019
Jul 2019
Historique:
received:
18
04
2019
revised:
28
05
2019
accepted:
06
06
2019
pubmed:
18
6
2019
medline:
18
12
2019
entrez:
18
6
2019
Statut:
ppublish
Résumé
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. FUND: This study was funded by an mRACE Erasmus MC grant.
Sections du résumé
BACKGROUND
BACKGROUND
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.
METHODS
METHODS
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.
FINDINGS
RESULTS
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.
INTERPRETATION
CONCLUSIONS
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. FUND: This study was funded by an mRACE Erasmus MC grant.
Identifiants
pubmed: 31204276
pii: S2352-3964(19)30382-2
doi: 10.1016/j.ebiom.2019.06.007
pmc: PMC6642075
pii:
doi:
Substances chimiques
Phosphodiesterase 5 Inhibitors
0
RNA, Messenger
0
Vinca Alkaloids
0
Nitric Oxide
31C4KY9ESH
vinpocetine
543512OBTC
Sildenafil Citrate
BW9B0ZE037
Nitric Oxide Synthase Type II
EC 1.14.13.39
Cyclic Nucleotide Phosphodiesterases, Type 1
EC 3.1.4.17
Cyclic Nucleotide Phosphodiesterases, Type 5
EC 3.1.4.35
Cyclic GMP
H2D2X058MU
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
447-455Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019. Published by Elsevier B.V.
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