Effect of sildenafil citrate on circulating levels of sFlt-1 in preeclampsia

Brownfoot, Fiona; Tong, Stephen; Hannan, Natalie J.; Cannon, Ping; Nguyen, Vi; Kaitu’u-Lino, Tu’uhevaha J

doi:10.1016/j.preghy.2018.04.011

Cited by 9 publications

(6 citation statements)

References 12 publications

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“…During a recent phase 2 randomized controlled trial (RCT), they showed that women in the placebo cohort had a greater decline in PIGF levels than those receiving SC [ 58 ]. A clinical case study of a 26-year-old woman with severe preeclampsia showed that SC increased the PLGF level measured in the serum [ 59 ]. Our RPL group of patients had lower concentrations of PIGF than the fertile group of women, which was not reflected in gene expression and SC improved the concentration of PLGF as in the mentioned studies.…”

Section: Discussionmentioning

confidence: 99%

Sildenafil Citrate Downregulates PDE5A mRNA Expression in Women with Recurrent Pregnancy Loss without Altering Angiogenic Factors—A Preliminary Study

Kniotek

Roszczyk

Zych

et al. 2021

JCM

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In our previous study, we showed that sildenafil citrate (SC), a selective PDE5A blocker, modulated NK cell activity in patients with recurrent pregnancy loss, which correlated with positive pregnancy outcomes. It was found that NK cells had a pivotal role in decidualization, angiogenesis, spiral artery remodeling, and the regulation of trophoblast invasion. Thus, in the current study, we determined the effects of SC on angiogenic factor expression and production, as well as idNK cell activity in the presence of nitric synthase blocker L-NMMA. Methods: NK cells (CD56+) were isolated from the peripheral blood of 15 patients and 15 fertile women on MACS columns and cultured in transformation media containing IL-15, TGF-β, and AZA—a methylation agent—for 7 days in hypoxia (94% N2, 1% O2, 5% CO2). Cultures were set up in four variants: (1) with SC, (2) without SC, (3) with NO, a synthase blocker, and (4) with SC and NO synthase blocker. NK cell activity was determined after 7 days of culturing as CD107a expression after an additional 4h of stimulation with K562 erythroleukemia cells. The expression of the PDE5A, VEGF-A, PIGF, IL-8, and RENBP genes was determined with quantitative real-time PCR (qRT-PCR) using TaqMan probes and ELISA was used to measure the concentrations of VEGF-A, PLGF, IL-8, Ang-I, Ang-II, IFN–γ proteins in culture supernatants after SC supplementation. Results: SC downregulated PDE5A expression and had no effect on other studied angiogenic factors. VEGF-A expression was increased in RPL patients compared with fertile women. Similarly, VEGF production was enhanced in RPL patients’ supernatants and SC increased the concentration of PIGF in culture supernatants. SC did not affect the expression or concentration of other studied factors, nor idNK cell activity, regardless of NO synthase blockade.

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Section: Discussionmentioning

confidence: 99%

Sildenafil Citrate Downregulates PDE5A mRNA Expression in Women with Recurrent Pregnancy Loss without Altering Angiogenic Factors—A Preliminary Study

Kniotek

Roszczyk

Zych

et al. 2021

JCM

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“…Therefore, it is necessary to identify the risk group for preeclampsia and/or fetal growth restriction, a condition that is fortunately possible, based on the levels of angiogenic factors in maternal blood and uterine Doppler flow [37]. Besides that, Brownfoot et al reported that sildenafil is associated with a reduction in circulating sFlt-1 levels in a patient with preterm preeclampsia [38].…”

Section: Discussionmentioning

confidence: 99%

The effects of sildenafil in maternal and fetal outcomes in pregnancy: A systematic review and meta-analysis

et al. 2019

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Background The number of studies associating the use of sildenafil in gestation is increasing. This drug inhibits phosphodiesterase type 5 (PDE5), an enzyme responsible for degradation of nitric oxide, and its efficacy is greater in the placental territory, as the maternal side of the placenta have more PDE5 than other sites. For this reason, promising results have been observed related to the prevention of preeclampsia and intrauterine growth restriction and to improvement of maternal-fetal morbidity in cases of placental insufficiency. Objective To evaluate the benefits of using sildenafil in pregnancy. Searched strategy MEDLINE, ClinicalTrials.gov, Embase, LILACS and Cochrane databases were searched through September 2018. There was no restriction in language or year of publication. This study was registered in PROSPERO (CRD42017060288). Selection criteria Randomized clinical trials which used sildenafil for treatment or prevention of obstetric diseases compared with placebo were selected. Data collection and analysis The results were obtained using the inverse variance method for continuous variables and Man-Whitney for categorical variables. Main results Among a population of 598 pregnant women from the seven clinical trials included, 139 had pre-eclampsia, 275 had intrauterine growth restriction, and 184 had oligohydramnios. A significant increase of 222.58 grams [27.75 to 417.41] was observed in the fetal weight at birth of patients taking sildenafil. The other outcomes did not show any statistical significance. This may be due to the small number of patients used in each study and the great heterogeneity between the groups. Conclusions Sildenafil could be associated with increasing fetal weight at birth in placental insufficiency despite the limitations of this meta-analysis, even though more studies in this field are needed to introduce this drug into obstetric clinical practice.

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“…Randomized controlled trials showed beneficial clinical effects, including mild prolongation of pregnancy, reduced uteroplacental arterial resistance , and reduction of maternal mean arterial pressure (MAP) [48]. Importantly, sildenafil has been shown to significantly reduce the level of sFlt-1 in maternal circulation [16].…”

Section: Discussionmentioning

confidence: 99%

“…Therapeutic oral doses of sildenafil demonstrate the ability to cause local vasorelaxation to improve fetoplacental perfusion while producing only a modest and transient decrease in systemic BP [31]. Furthermore, a reduction in endogenous NO production has been identified in preeclampsia, and sildenafil has been shown to attenuate pathogenesis of this disease [16,17,43]. We have previously shown that sildenafil attenuates the maternal phenotype of preeclampsia and results in improved pup growth and increased litter size in the Dahl SS/Jr rat, an established model of spontaneous, superimposed preeclampsia [26,27].…”

Section: Introductionmentioning

confidence: 99%

Sildenafil Citrate Does Not Reprogram Risk of Hypertension and Chronic Kidney Disease in Offspring of Preeclamptic Pregnancies in the Dahl SS/Jr Rat

et al. 2020

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Background: Preeclampsia is a disorder of pregnancy with high disease and economic burdens in the United States. Evidence supporting longstanding effects of preeclampsia on the offspring of affected pregnancies is high, but the effects of current antihypertensive therapies for preeclampsia on cardio-renal outcomes are largely unknown. The purpose of this study was to test the hypothesis that sildenafil citrate, a phosphodiesterase-5 inhibitor, reprograms the risk of hypertension and kidney disease in offspring of preeclamptic pregnancies by altering responses to secondary stressors. Methods: Dahl SS/Jr rats on a 0.3% NaCl diet were mated. At gestational day 10, pregnant dams were randomized to vehicle diet or diet with sildenafil (50 mg/kg/day), which was continued until birth. Pups were weaned at four weeks of age and allowed to age on a 0.3% NaCl diet until three months of age. At this point, pups were randomized into three groups: baseline or no intervention, 2% NaCl diet challenge for four weeks, or a subpressor infusion of angiotensin II (200 ng/kg/min) for two weeks. Results: There were no differences among maternal treatment groups at baseline. Upon introduction of 2% NaCl diet, male offspring of SLD-treated dams exhibited an attenuated rise in BP; however, this protection was not observed during Ang II infusion. Conclusions: Our findings indicate that intrapartum sildenafil does not reprogram the risk of hypertension and kidney disease in offspring of preeclamptic pregnancies. (BP) during childhood and into adulthood [3,4]. This hypothesis, the Developmental Origins of Health and Disease (DOHaD) theory, proposes that an adverse intrauterine environment (insufficient nutrition or blood flow to the fetus) results in epigenetic changes that alter metabolism and physiologic response mechanisms, throughout the life of the offspring [5,7]. Further studies and meta-analyses showed that children born after preeclamptic pregnancies are at greater risk for vascular diseases such as hypertension and stroke [23,24,33]. While several proposed mechanisms for this link have gained evidentiary support [12,13,32,37], the exact nature of this pathogenesis remains unknown, so no potential therapeutic interventions have been shown. Despite increasing research for potential preeclampsia treatments, the current standard of care is limited to careful monitoring, limited antihypertensive treatment, magnesium sulfate infusion for prevention of eclamptic seizures, and early delivery [1]. While continued gestation is usually beneficial for fetal development, continued exposure to an intrauterine environment with suboptimal nutrition conveys additional risk [2,6].Experimental therapies currently being tested include antioxidants (ex.

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Effect of sildenafil citrate on circulating levels of sFlt-1 in preeclampsia

Cited by 9 publications

References 12 publications

Sildenafil Citrate Downregulates PDE5A mRNA Expression in Women with Recurrent Pregnancy Loss without Altering Angiogenic Factors—A Preliminary Study

Sildenafil Citrate Downregulates PDE5A mRNA Expression in Women with Recurrent Pregnancy Loss without Altering Angiogenic Factors—A Preliminary Study

The effects of sildenafil in maternal and fetal outcomes in pregnancy: A systematic review and meta-analysis

Sildenafil Citrate Does Not Reprogram Risk of Hypertension and Chronic Kidney Disease in Offspring of Preeclamptic Pregnancies in the Dahl SS/Jr Rat

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