sildenafil-citrate and Pre-Eclampsia

Sildenafil, a phosphodiesterase 5 inhibitor with a vasodilatory and anti-remodeling effect, has been investigated concerning various conditions during pregnancy. Per indication, we herein review the rationale and the most relevant experimental and clinical studies, including systematic reviews and meta-analyses, when available. Indications for using sildenafil during the second and third trimester of pregnancy include maternal pulmonary hypertension, preeclampsia, preterm labor, fetal growth restriction, oligohydramnios, fetal distress, and congenital diaphragmatic hernia. For most indications, the rationale for administering prenatal sildenafil is based on limited, equivocal data from in vitro studies and rodent disease models. Clinical studies report mild maternal side effects and suggest good fetal tolerance and safety depending on the underlying pathology.

Topics: Female; Fetal Growth Retardation; Hernias, Diaphragmatic, Congenital; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Pre-Eclampsia; Pregnancy; Sildenafil Citrate

Preeclampsia is a hypertensive disorder of pregnancy and the clinical manifestation of severe endothelial dysfunction associated with maternal and foetal morbidity and mortality. The primum movens of the disease is the defect of invasion of the uterine arteries by foetal syncytiotrophoblasts, which causes a maladaptive placental response to chronic hypoxia and the secretion of the soluble form of type 1 vascular growth endothelial factor receptor, also called soluble fms-like tyrosine kinase 1 (sFlt-1), the major player in the pathophysiology of the disease. Among its different effects, sFlt-1 induces abnormal sensitivity of the maternal vessels to the vasoconstrictor angiotensin II. This leads to the hypertensive phenotype, recently shown to be abrogated by the administration of sildenafil citrate, which can potentiate the vasodilatory mediator nitrite oxide. This review focuses on the mechanisms of maternal endothelial dysfunction in preeclampsia and discusses the therapeutic window of sildenafil use in the context of preeclampsia, based on the results from preclinical studies and clinical trials. Safety issues recently reported in neonates have considerably narrowed this window.

Topics: Dose-Response Relationship, Drug; Endothelium, Vascular; Female; Humans; Infant, Newborn; Pre-Eclampsia; Pregnancy; Sildenafil Citrate

Pre-eclampsia is a serious multisystem disorder with diverse clinical manifestations. Although not causal, endothelial dysfunction and reduced nitric oxide bioavailability are likely to play an important role in the maternal and fetal pathophysiology of this condition. Lack of treatment modalities that can target the underlying pathophysiological changes and reverse the endothelial dysfunction frequently leads to iatrogenic preterm delivery of the fetus, causing neonatal morbidity and mortality, and the condition itself is associated with short- and longer term maternal morbidity and mortality. Drugs that target various components of the nitric oxide-soluble guanylyl cyclase pathway can help to increase NO bioavailability. The purpose of this review is to outline the current status of clinical research involving these therapeutic modalities in the context of pre-eclampsia, with the focus being on the following: nitric oxide donors, including organic nitrates and S-nitrosothiols; l-arginine, the endogenous precursor of NO; inhibitors of cyclic guanosine 3',5'-monophosphate breakdown, including sildenafil; and other novel inhibitors of NO donor metabolism. The advantages and limitations of each modality are outlined, and scope for development into established therapeutic options for pre-eclampsia is explored.

Topics: Aldehyde Oxidoreductases; Clinical Trials as Topic; Endothelium, Vascular; Female; Humans; Isosorbide Dinitrate; Nitric Oxide; Nitric Oxide Donors; Nitroglycerin; Phosphodiesterase Inhibitors; Piperazines; Pre-Eclampsia; Pregnancy; Purines; S-Nitrosothiols; Sildenafil Citrate; Sulfonamides

Pre-eclampsia and intrauterine growth restriction (IUGR) are responsible for approximately 15-20% of serious maternal and neonatal diseases. These complications are related to very early anomalies of the uteroplacental circulation, accompanied, at least secondarily, by thromboxane-prostacyclin-related imbalances. Studies have failed to show a beneficial effect of betamimetics and calcium channel blockers for the treatment of IUGR. Sildenafil citrate, a type 5-specific phosphodiesterase inhibitor, augments the vasodilatory effects of NO by preventing the degradation of cGMP There is a selective effect of Sildenafil on the uteroplacental circulation. Sildenafil improves uterine artery blood flow.

Topics: Female; Fetal Growth Retardation; Humans; Phosphodiesterase 5 Inhibitors; Piperazines; Pre-Eclampsia; Pregnancy; Purines; Sildenafil Citrate; Sulfones; Vasodilator Agents

Preeclampsia is a pregnancy-induced hypertensive disorder found most commonly in nulliparous women. Recent research performed in animal models of the disease has revealed some of the underlying mechanisms of preeclampsia. Specifically, placental insufficiency and the resulting hypoxia/ischemia have been shown to be crucial to disease progression. In response to placental hypoxia/ischemia, several pathways are activated, which contribute to the clinical manifestations of the disease: increased circulating levels of the anti-angiogenic protein sFlt-1, activation of the maternal inflammatory response, suppressed nitric oxide production, enhanced endothelin-1 production, and induction of reactive oxygen formation. Despite advances in the understanding of the disorder, therapeutic approaches to the treatment of preeclampsia are severely limited. New lines of research, however, indicate some possible new therapeutic approaches for the management of preeclampsia and offer hope for an effective pharmacologic intervention.

Topics: Disease Progression; Endothelin-1; Endothelium, Vascular; Female; Humans; Hypoxia; Inflammation; Phosphodiesterase 5 Inhibitors; Piperazines; Placenta; Pre-Eclampsia; Pregnancy; Purines; Risk Factors; Sildenafil Citrate; Sulfones; Vascular Endothelial Growth Factor A

Severe early onset fetal growth restriction caused by placental dysfunction leads to high rates of perinatal mortality and neonatal morbidity. The phosphodiesterase 5 inhibitor, sildenafil, inhibits cyclic guanosine monophosphate hydrolysis, thereby activating the effects of nitric oxide, and might improve uteroplacental function and subsequent perinatal outcomes.. To determine whether sildenafil reduces perinatal mortality or major morbidity.. This placebo-controlled randomized clinical trial was conducted at 10 tertiary referral centers and 1 general hospital in the Netherlands from January 20, 2015, to July 16, 2018. Participants included pregnant women between 20 and 30 weeks of gestation with severe fetal growth restriction, defined as fetal abdominal circumference below the third percentile or estimated fetal weight below the fifth percentile combined with Dopplers measurements outside reference ranges or a maternal hypertensive disorder. The trial was stopped early owing to safety concerns on July 19, 2018, whereas benefit on the primary outcome was unlikely. Data were analyzed from January 20, 2015, to January 18, 2019. The prespecified primary analysis was an intention-to-treat analysis including all randomized participants.. Participants were randomized to sildenafil, 25 mg, 3 times a day vs placebo.. The primary outcome was a composite of perinatal mortality or major neonatal morbidity until hospital discharge.. Out of 360 planned participants, a total of 216 pregnant women were included, with 108 women randomized to sildenafil (median gestational age at randomization, 24 weeks 5 days [interquartile range, 23 weeks 3 days to 25 weeks 5 days]; mean [SD] estimated fetal weight, 458 [160] g) and 108 women randomized to placebo (median gestational age, 25 weeks 0 days [interquartile range, 22 weeks 5 days to 26 weeks 3 days]; mean [SD] estimated fetal weight, 464 [186] g). In July 2018, the trial was halted owing to concerns that sildenafil may cause neonatal pulmonary hypertension, whereas benefit on the primary outcome was unlikely. The primary outcome, perinatal mortality or major neonatal morbidity, occurred in the offspring of 65 participants (60.2%) allocated to sildenafil vs 58 participants (54.2%) allocated to placebo (relative risk, 1.11; 95% CI, 0.88-1.40; P = .38). Pulmonary hypertension, a predefined outcome important for monitoring safety, occurred in 16 neonates (18.8%) in the sildenafil group vs 4 neonates (5.1%) in the placebo group (relative risk, 3.67; 95% CI, 1.28-10.51; P = .008).. These findings suggest that antenatal maternal sildenafil administration for severe early onset fetal growth restriction did not reduce the risk of perinatal mortality or major neonatal morbidity. The results suggest that sildenafil may increase the risk of neonatal pulmonary hypertension.. ClinicalTrials.gov Identifier: NCT02277132.

Topics: Adult; Birth Weight; Double-Blind Method; Early Termination of Clinical Trials; Female; Fetal Growth Retardation; Gestational Age; Humans; Hypertension, Pulmonary; Infant, Newborn; Infant, Newborn, Diseases; Intention to Treat Analysis; Male; Middle Cerebral Artery; Perinatal Mortality; Phosphodiesterase 5 Inhibitors; Placenta Diseases; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Pulsatile Flow; Sildenafil Citrate; Umbilical Arteries

To assess the effect of maternal sildenafil therapy on fetal growth in pregnancies with early-onset fetal growth restriction.. A randomised placebo-controlled trial.. Thirteen maternal-fetal medicine units across New Zealand and Australia.. Women with singleton pregnancies affected by fetal growth restriction at 22. Women were randomised to oral administration of 25 mg sildenafil citrate or visually matching placebo three times daily until 32. The primary outcome was the proportion of pregnancies with an increase in fetal growth velocity. Secondary outcomes included live birth, survival to hospital discharge free of major neonatal morbidity and pre-eclampsia.. Sildenafil did not affect the proportion of pregnancies with an increase in fetal growth velocity; 32/61 (52.5%) sildenafil-treated, 39/57 (68.4%) placebo-treated [adjusted odds ratio (OR) 0.49, 95% CI 0.23-1.05] and had no effect on abdominal circumference Z-scores (P = 0.61). Sildenafil use was associated with a lower mean uterine artery pulsatility index after 48 hours of treatment (1.56 versus 1.81; P = 0.02). The live birth rate was 56/63 (88.9%) for sildenafil-treated and 47/59 (79.7%) for placebo-treated (adjusted OR 2.50, 95% CI 0.80-7.79); survival to hospital discharge free of major neonatal morbidity was 42/63 (66.7%) for sildenafil-treated and 33/59 (55.9%) for placebo-treated (adjusted OR 1.93, 95% CI 0.84-4.45); and new-onset pre-eclampsia was 9/51 (17.7%) for sildenafil-treated and 14/55 (25.5%) for placebo-treated (OR 0.67, 95% CI 0.26-1.75).. Maternal sildenafil use had no effect on fetal growth velocity. Prospectively planned meta-analyses will determine whether sildenafil exerts other effects on maternal and fetal/neonatal wellbeing.. Maternal sildenafil use has no beneficial effect on growth in early-onset FGR, but also no evidence of harm.

Topics: Adult; Australia; Female; Fetal Growth Retardation; Gestational Age; Humans; Infant, Newborn; Live Birth; New Zealand; Phosphodiesterase 5 Inhibitors; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Sildenafil Citrate; Treatment Outcome

To evaluate whether therapy with sildenafil citrate prolongs gestation in women with preeclampsia.. In a randomized double-blind, placebo-controlled trial, 100 singleton pregnancies with preeclampsia between 24 and 33 weeks of gestation were randomized to 50 mg oral sildenafil citrate every 8 hours or placebo. The primary outcome was prolongation of pregnancy from randomization to delivery. Secondary outcomes were changes in resistance indices of uterine, umbilical, and middle cerebral arteries by Doppler, fetal and maternal complications, and adverse neonatal outcomes. Power analysis estimated that to detect a difference of 5 days in pregnancy duration, 43 patients would have to be randomized to each group.. From June 2013 to October 2015, 50 patients were randomized to each group. Pregnancy duration was on average 4 days longer (14.4 days, 95% confidence interval [CI] 12.5-16.6 days compared with 10.4 days, 95% CI 8.4-12.3 days, P=.008) and percent reduction in pulsatility indices of uterine and umbilical arteries higher (22.5% and 18.5%, compared with placebo 2.1% and 2.5%, P<.001) for patients treated with sildenafil compared with placebo. Maternal blood pressure before and 24 hours after randomization was lower with sildenafil (sildenafil: 100.3±5.6 mm Hg compared with 116.4±5.1 mm Hg, P<.05; placebo: 110.6±6.2 mm Hg compared with 114.7±6.5 mm Hg, P=.21). There was no difference in perinatal morbidity, mortality, or adverse effects between groups.. Therapy with sildenafil citrate was associated with pregnancy prolongation of approximately 4 days compared with placebo in women with preeclampsia.. Brazilian Registry of Clinical Trials, www.ensaiosclinicos.gov.br, RBR-8qj4p5.

Topics: Adult; Blood Flow Velocity; Blood Pressure; Double-Blind Method; Female; Gestational Age; Humans; Middle Cerebral Artery; Phosphodiesterase 5 Inhibitors; Pre-Eclampsia; Pregnancy; Pregnancy Maintenance; Sildenafil Citrate; Time Factors; Ultrasonography, Doppler; Umbilical Arteries; Uterine Artery; Vascular Resistance; Young Adult

To determine if the phosphodiesterase type 5 inhibitor sildenafil prolongs pregnancy in women with preeclampsia.. Women with preeclampsia at gestational ages 24-34 weeks were recruited from nine hospitals in the UK, and randomly assigned to sildenafil citrate or placebo. Medication was increased every 3 days from 20 mg three times daily (tid), to 40 mg, and 80 mg tid. The primary endpoint was prolongation of pregnancy from randomisation to delivery (days). Secondary endpoints were markers of maternal disease and cord pH at delivery and infant weight. Details of all adverse events were also collected. Plasma samples were taken to establish pharmacokinetic information. Data analysed on a modified intention to treat analysis. The study had a power of >95% to detect a difference of 5 days.. Of 35 women, 17 were allocated to sildenafil and 18 to placebo. There was no difference in time from randomisation to delivery in the two treatment groups, with a median time of 4 days (range 1-15) in the sildenafil group and 4.5 days (range 1-30) in the placebo group. Sildenafil achieved maximum drug concentrations of 48 ng/ml, 88 ng/ml, and 271 ng/ml after 3 days of 20 mg, 40 mg and 80 mg tid, respectively.. We have safely conducted a clinical trial of a drug not routinely used during pregnancy. Sildenafil in the escalating dose regimen 20-80 mg tid was well tolerated, with no increase in maternal or fetal morbidity or mortality but did not prolong pregnancy duration in women with preeclampsia. (ClinicalTrials.gov number, NCT 00141310).

Topics: Adult; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Intention to Treat Analysis; Patient Selection; Phosphodiesterase Inhibitors; Piperazines; Pre-Eclampsia; Pregnancy; Purines; Sildenafil Citrate; Sulfones; Treatment Outcome

There is a lack of effective therapeutic interventions for preeclampsia. A central factor in the etiology of the disease is the development of placental hypoxia due to abnormal vascular remodeling. However, methods to assess the impact of potential therapies on placental growth and remodeling are currently lacking. Here, we develop and validate ultrasound-guided photoacoustic imaging methods to monitor the placental response to therapeutic intervention. Establishing non-invasive tools to image placental function opens up previously unachievable understandings of placental therapeutic response.. Studies were performed in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia. Preclinical research has identified tempol, a superoxide dismutase mimetic, and the phosphodiesterase inhibitor sildenafil as potential therapeutics for preeclampsia, as both improve in vivo maternal outcomes. PA images of the placental environment were acquired in RUPP rats receiving tempol (n = 8) or sildenafil (n = 8) to assess the longitudinal effects of treatment on placental oxygenation and vascular remodeling. Imaging measurements were validated with ex vivo histological analysis.. Spectral photoacoustic imaging non-invasively measured placental hypoxia and impaired vascular growth two days after the RUPP procedure was implemented. Sildenafil significantly improved (p < 0.05) placental oxygenation and promoted vascular remodeling in RUPP animals, while RUPP animals treated with tempol had a diminished placental therapeutic response.. We demonstrate that photoacoustic imaging provides in vivo measures of placental oxygenation and vascular remodeling, a previously unobtainable assessment of preeclamptic therapeutic response. These imaging tools have tremendous potential to accelerate the search for effective therapies for preeclampsia.

Topics: Animals; Disease Models, Animal; Female; Humans; Hypoxia; Ischemia; Photoacoustic Techniques; Placenta; Pre-Eclampsia; Pregnancy; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Vascular Remodeling

Preeclampsia is a disorder of pregnancy with accompanying 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.. 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 per day), which was continued until birth. Pups were weaned at 4 weeks of age and allowed to age on a 0.3% NaCl diet until 3 months of age. At this point, pups were randomized into three groups: baseline or no intervention, 2% NaCl diet challenge for 4 weeks, or a subpressor infusion of angiotensin II (200 ng/kg per minute) for 2 weeks.. There were no differences among maternal treatment groups at baseline. Upon introduction of 2% NaCl diet, male offspring of sildenafil-treated dams exhibited an attenuated rise in BP; however, this protection was not observed during angiotensin II infusion.. Our findings indicate that intrapartum sildenafil does not reprogram the risk of hypertension and kidney disease in offspring of preeclamptic pregnancies.

Topics: Animals; Female; Hypertension; Male; Pre-Eclampsia; Pregnancy; Rats; Rats, Inbred Dahl; Renal Insufficiency, Chronic; Sildenafil Citrate

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.

Topics: Adult; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 1; Cyclic Nucleotide Phosphodiesterases, Type 5; Female; Humans; Nitric Oxide; Nitric Oxide Synthase Type II; Phosphodiesterase 5 Inhibitors; Placenta; Pre-Eclampsia; Pregnancy; RNA, Messenger; Sildenafil Citrate; Vasodilation; Vinca Alkaloids

Topics: Case-Control Studies; Female; Humans; Placenta; Pre-Eclampsia; Pregnancy; Sildenafil Citrate

To examine the effect of sildenafil on level of antiangiogenic proteins of preeclampsia. Firstly to examine the effect of sildenafil on serum biomarkers in a patient with preterm preeclampsia. Secondly, to examine the effect of sildenafil on sFlt-1 and soluble endoglin secretion from primary trophoblasts and placental explants.. The clinical team administered 50 mg tds sildenafil to a 26-year-old primigravid woman with severe preeclampsia at the threshold of viability (24 3/7 weeks gestation) and we collected bloods to examine the effect of slidenafil on antiangiogenic factors sFlt-1 and soluble endoglin (sENG), pro-angiogenic factor PlGF and vascular cell adhesion molecule 1 (VCAM-1) and endothelin-1 (ET1). We administered sildenafil to human primary trophoblasts and placental explants and explored its effect on sFlt-1 and sENG secretion.. We examined serum anti-angiogenic factors sFlt-1 and sENG, pro-angiogenic factor PlGF, the potent vasoconstrictor ET1 and VCAM-1 by ELISA. We explored the effect of sildenafil on sFlt-1 secretion from primary trophoblasts and sFlt-1 and sENG secretion from placental explants.. We found a reduction in serum sFlt-1, stabilisation in sENG and PlGF in a patient with peri-viable preterm preeclampsia administered oral sildenafil 50 mg three times daily (tds). Furthermore there was an initial stabilisation in serum VCAM-1 and a decline in ET1 with sildenafil administration. This was concordant with stabilisation of clinical and biochemical features of preeclampsia. Interestingly, treating placental cells and tissues in vitro with sildenafil did not appear to change sFlt-1 or sENG secretion.. Sildenafil administration was associated with a reduction in serum sFlt-1 and sENG secretion and increase in PlGF secretion in a patient with preterm preeclampsia, potentially via increasing placental perfusion rather than acting directly on the placenta.

Topics: Administration, Oral; Adult; Biomarkers; Female; Humans; Placenta; Pre-Eclampsia; Pregnancy; Sildenafil Citrate; Trophoblasts; Vascular Endothelial Growth Factor Receptor-1; Vasodilator Agents

Pre-eclampsia (PE), a hypertensive disorder of pregnancy, is detrimental to both mother and foetus. There is currently no effective treatment, but we have shown that Sildenafil Citrate (SC) improve various foetal outcomes in N

Topics: Animals; Biomarkers; Blood Pressure; Disease Models, Animal; Female; Gene Expression Regulation; Inflammation; Interferon-gamma; Neovascularization, Physiologic; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pre-Eclampsia; Pregnancy; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sildenafil Citrate; Time Factors; Transforming Growth Factor beta; Uterus; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

Topics: Animals; Disease Models, Animal; Female; Gene Expression Regulation; Humans; Intracellular Signaling Peptides and Proteins; Kidney; Membrane Proteins; NG-Nitroarginine Methyl Ester; Pre-Eclampsia; Pregnancy; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sildenafil Citrate

Preeclampsia, a hypertensive disorder of pregnancy, is detrimental to both mother and fetus. There is currently no effective treatment, but sildenafil, a phosphodiesterase-5 inhibitor, has been proposed as a potential therapy to reduce blood pressure and improve uteroplacental perfusion in preeclamptic patients. We hypothesized that sildenafil would improve the maternal syndrome and fetal outcomes in the Dahl S rat model of superimposed preeclampsia. Dahl S rats were mated, and half received sildenafil (50 mg/kg per day, via food) from day 10 through day 20 of pregnancy. The untreated Dahl S rats had a significant rise in blood pressure and a 2-fold increase in urinary protein excretion from baseline to late pregnancy; however, sildenafil-treated Dahl S rats exhibited ≈40 mm Hg drops in blood pressure with no rise in protein excretion. Sildenafil also increased creatinine clearance and reduced nephrinuria and glomerulomegaly. Sildenafil treatment reduced the uterine artery resistance index during late pregnancy in the Dahl S rat and improved fetal outcomes (survival, weight, and litter size). In addition, 19% of all pups were resorbed in untreated rats, with no incidence of resorptions observed in the treated group. Furthermore, tumor necrosis factor-α, endothelin-1, and oxidative stress, which are characteristically increased in women with preeclampsia and in experimental models of the disease, were reduced in treated rats. These data suggest that sildenafil improves the maternal syndrome of preeclampsia and blood flow to the fetoplacental unit, providing preclinical evidence to support the hypothesis that phosphodiesterase type 5 inhibition may be an important therapeutic target for the treatment of preeclampsia.

Topics: Animals; Blood Pressure; Disease Models, Animal; Female; Fetal Development; Pre-Eclampsia; Pregnancy; Pregnancy, Animal; Rats; Rats, Inbred Dahl; Sildenafil Citrate; Syndrome; Vascular Resistance; Vasodilator Agents

Preeclampsia is a hypertensive disorder of pregnancy in which patients develop profound sensitivity to vasopressors, such as angiotensin II, and is associated with substantial morbidity for the mother and fetus. Enhanced vasoconstrictor sensitivity and elevations in soluble fms-like tyrosine kinase 1 (sFLT1), a circulating antiangiogenic protein, precede clinical signs and symptoms of preeclampsia. Here, we report that overexpression of sFlt1 in pregnant mice induced angiotensin II sensitivity and hypertension by impairing endothelial nitric oxide synthase (eNOS) phosphorylation and promoting oxidative stress in the vasculature. Administration of the NOS inhibitor l-NAME to pregnant mice recapitulated the angiotensin sensitivity and oxidative stress observed with sFlt1 overexpression. Sildenafil, an FDA-approved phosphodiesterase 5 inhibitor that enhances NO signaling, reversed sFlt1-induced hypertension and angiotensin II sensitivity in the preeclampsia mouse model. Sildenafil treatment also improved uterine blood flow, decreased uterine vascular resistance, and improved fetal weights in comparison with untreated sFlt1-expressing mice. Finally, sFLT1 protein expression inversely correlated with reductions in eNOS phosphorylation in placental tissue of human preeclampsia patients. These data support the concept that endothelial dysfunction due to high circulating sFLT1 may be the primary event leading to enhanced vasoconstrictor sensitivity that is characteristic of preeclampsia and suggest that targeting sFLT1-induced pathways may be an avenue for treating preeclampsia and improving fetal outcomes.

Topics: Angiotensin II; Angiotensins; Animals; Blood Pressure; Disease Models, Animal; Female; Humans; Male; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase Type III; Oxidative Stress; Phosphorylation; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy, Animal; Signal Transduction; Sildenafil Citrate; Treatment Outcome; Vascular Endothelial Growth Factor Receptor-1

Topics: Double-Blind Method; Female; Hemodynamics; Humans; Parturition; Pre-Eclampsia; Pregnancy; Sildenafil Citrate

N(omega)-nitro-L-arginine methyl ester (L-NAME) decreases the vasodilator effect of nitric oxide (NO) and induces pre-eclampsia in mouse. Sildenafil inhibits the degradation of nitric oxide and increases vasodilation. This study aimed to determine the effects of sildenafil citrate on angiogenesis and oxidative stress at the maternal foetal interface on pre-eclampsia-like mouse model induced by L-NAME. Twenty pregnant mice were divided into four groups: (i) vehicle control; (ii) L-NAME; (iii) sildenafil; (4) L-NAME+sildenafil. L-NAME was administered from day 7 of pregnancy and sildenafil from day 8 until day 16; animals were euthanized on day 17. Placental and foetal sizes and weights were measured; lipid peroxide levels and catalase activity in placental homogenates were determined, and placental vascular endothelia were identified by lectin-histochemistry using BSA-I lectin. Western blot analysis was used to determine VEGF expression in placental homogenates. No changes were seen in placental and foetal development in mice with normal pregnancies treated with sildenafil. Treatments with L-NAME reduced significantly the placental weight and average height and decreased the percentage of the endothelial surface. These alterations may be mediated by the reduction of NO levels in trophoblastic cells, due to the inhibitory effect of L-NAME on nitric oxide synthase (NOS) synthesis. This effect was offset by the treatment with sildenafil, with an increase in the percentage of the endothelial surface. In conclusion, our results indicate that treatment with sildenafil on pre-eclampsia mouse model can be used without adverse effects on the concept and its use in the treatment of pre-eclampsia is promising.

Topics: Animals; Disease Models, Animal; Female; Fetus; Mice; Mice, Inbred BALB C; Neovascularization, Physiologic; NG-Nitroarginine Methyl Ester; Oxidative Stress; Placenta; Pre-Eclampsia; Pregnancy; Sildenafil Citrate; Vasodilator Agents

Preeclampsia (PE) and fetal growth restriction (FGR) are serious complications of pregnancy, associated with greatly increased risk of maternal and perinatal morbidity and mortality. These complications are difficult to diagnose and no curative treatments are available. We hypothesized that the metabolomic signature of two models of disease, catechol-O-methyl transferase (COMT(-/-)) and endothelial nitric oxide synthase (Nos3(-/-)) knockout mice, would be significantly different from control C57BL/6J mice. Further, we hypothesised that any differences in COMT(-/-) mice would be resolved following treatment with Sildenafil, a treatment which rescues fetal growth. Targeted, quantitative comparisons of serum metabolic profiles of pregnant Nos3(-/-), COMT(-/-) and C57BL/6J mice were made using a kit from BIOCRATES. Significant differences in 4 metabolites were observed between Nos3(-/-) and C57BL/6J mice (p < 0.05) and in 18 metabolites between C57BL/6J and COMT(-/-) mice (p < 0.05). Following treatment with Sildenafil, only 5 of the 18 previously identified differences in metabolites (p < 0.05) remained in COMT(-/-) mice. Metabolomic profiling of mouse models is possible, producing signatures that are clearly different from control animals. A potential new treatment, Sildenafil, is able to normalize the aberrant metabolomic profile in COMT(-/-) mice; as this treatment moves into clinical trials, this information may assist in assessing possible mechanisms of action.

Topics: Animals; Catechol O-Methyltransferase; Disease Models, Animal; Female; Fetal Growth Retardation; Metabolome; Metabolomics; Mice; Mice, Knockout; Pre-Eclampsia; Pregnancy; Sildenafil Citrate

In order to address the gap in our understanding of the pathogenesis and pathophysiology of PE, we optimized the NOS inhibition animal model by comparing changes in different parameters at various time frames during pregnancy, in both early and late-onset PE.. 120 nulliparous Sprague-Dawley rats were divided into 5 groups (n=24). A pregnant control, two groups that represented early and late-onset PE and two groups that were treated with sildenafil citrate (SC) to show reversal of the pre-eclamptic-like symptoms.. Our results showed that treatment with L-NAME caused significant changes in physiological parameters for both early and late-onset PE groups. There was a significant increase in systolic blood pressure (SBP) levels in the early-onset PE group (128.5±5.71 mmHg) and late-onset PE group (128.3±6.15 mmHg) on day 19 compared to the SBPs on day 0, (p<0.01). Urine excretion volumes in the early-onset PE group (13.62±3.18 mL) and in the late-onset PE (13.28±2.60 mL), compared to the pregnant control group (11.96±1.9 mL) were also increased (p<0.05). There was also an increase in total urinary protein in the early-onset PE group (0.62±0.08 g/L and the late-onset PE group (0.45±0.05 g/L), when compared to the pregnant control group (0.38±0.07) (p<0.05). We also found a decrease in fetal numbers in the PE group in comparison to the pregnant control and SC treated groups. The remission of these signs was seen after delivery of the fetuses. We also demonstrated that treatment of this syndrome with SC prevented the development of these signs.. The NOS inhibition model can be used for the study of the pathogenesis and pathophysiology of PE, since the pathogenic changes mimic those of early and late-PE.

Topics: Animals; Blood Pressure; Disease Models, Animal; Female; Fetal Weight; Litter Size; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Parturition; Piperazines; Pre-Eclampsia; Pregnancy; Proteinuria; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfonamides; Time Factors; Urine; Vasodilator Agents

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/β-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/μg 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/μg protein; P < 0.05). These data suggest that sildenafil might provide an effective therapeutic option for the management of hypertension during preeclampsia.

Topics: Actins; Administration, Oral; Animals; Antihypertensive Agents; Arterial Pressure; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Female; Ischemia; Kidney Medulla; Phosphodiesterase 5 Inhibitors; Piperazines; Placenta; Placental Circulation; Pre-Eclampsia; Pregnancy; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vasodilator Agents

Drug development in pregnancy and particularly in preeclampsia has been long neglected. Preeclampsia is a leading cause of maternal mortality, and early-onset preeclampsia can result in serious long-lasting consequences to the neonate. Many treatments have been trialed with varying success including vitamin supplementation, low-molecular-weight heparins, and aspirin. In this commentary, we particularly focus on the current status of drugs in development specifically aimed at preeclampsia. We outline the current understanding of the causes of the endothelial dysfunction seen in preeclampsia and, as such, potential therapeutic targets. With treatment of preeclampsia being largely unchanged in decades, there is an urgent need for novel therapies particularly those directed at the underlying causes that may allow for extremely preterm delivery, and its myriad consequences, to be avoided.

Topics: Endothelium, Vascular; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Nitric Oxide; Nitric Oxide Synthase Type III; Piperazines; Pre-Eclampsia; Pregnancy; Premature Birth; Purines; S-Nitrosoglutathione; Sildenafil Citrate; Sulfones; Vascular Endothelial Growth Factor A

We aimed to determine the effects of sildenafil in human umbilical artery preparation taken from preeclamptic or normal pregnant women, also to investigate underlying mechanisms in these effects.. Eighteen pregnant women with preeclampsia and 18 healthy pregnant women were involved. Relaxation responses of sildenafil in presence and absence of nitric oxide (NO) synthase inhibitor, N-[omega]-nitro-L-arginine methyl ester (L-NAME), and soluble guanylyl cyclase inhibitor, 1H-[1,2,4] oxadiazolo [4,3-a]quinoxalin-1-one (ODQ), were compared between the preeclampsia group and control group.. Sildenafil-induced relaxation responses were significantly attenuated in the presence of preeclampsia, L-NAME or ODQ, but not totally abolished. Interestingly, except with ODQ incubation, in all set of experiments maximal relaxation response was achieved by sildenafil.. These data indicate that sildenafil might effect vascular responsiveness of human umbilical artery through the involvement of NO/cyclic guanosine monophosphate (cGMP)-dependent and -independent pathways. Further investigations are needed to clarify the exact mechanisms.

Topics: Adolescent; Adult; Case-Control Studies; Endothelium, Vascular; Enzyme Inhibitors; Female; Guanylate Cyclase; Humans; In Vitro Techniques; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Oxadiazoles; Piperazines; Pre-Eclampsia; Pregnancy; Purines; Quinoxalines; Sildenafil Citrate; Sulfones; Umbilical Arteries; Vasodilation; Vasodilator Agents; Young Adult

Preeclampsia and fetal growth restriction are responsible for the majority of maternal and perinatal morbidity and mortality associated with complicated pregnancies. Although their etiologies are complex and multifactorial, both are associated with increased uterine artery resistance. Sildenafil citrate is able to rescue the dysfunction observed ex vivo in uterine arteries of women with preeclampsia. The ability of sildenafil citrate to increase uterine artery vasodilation, thereby decreasing uterine artery resistance and, hence, ameliorated preeclampsia and fetal growth restriction, was tested in a mouse model of preeclampsia, the catechol-O-methyl transferase knockout mouse (COMT(-/-)). COMT(-/-) and C57BL/6J mice were treated (0.2 mg/mL in drinking water, n=6-12) from gestational day 12.5 to 18.5. Measures of pup growth, including body weight, crown/rump length, and abdominal circumference, were reduced in COMT(-/-) mice; this was normalized after treatment with Sildenafil. COMT(-/-) mice also demonstrated abnormal umbilical Doppler waveforms, including reverse arterial blood flow velocity. This was normalized after treatment with Sildenafil. Abnormal uterine artery Doppler waveforms were not demonstrated in COMT(-/-) mice, although ex vivo responses of uterine arteries to phenylephrine were increased; moreover, treatment with Sildenafil did improve ex vivo sensitivity to an endothelium-dependent vasodilator. The data presented here demonstrate that Sildenafil can rescue pup growth and improve abnormal umbilical Doppler waveforms, providing support for a potential new therapeutic strategy targeting fetal growth restriction.

Topics: Animals; Blood Flow Velocity; Catechol O-Methyltransferase; Disease Models, Animal; Female; Fetal Growth Retardation; Hypertension; Mice; Mice, Inbred C57BL; Mice, Knockout; Myometrium; Piperazines; Pre-Eclampsia; Pregnancy; Proteinuria; Purines; Sildenafil Citrate; Sulfones; Ultrasonography, Doppler; Umbilical Arteries; Vasodilation; Vasodilator Agents

To assess the effect of sildenafil citrate in a rat model of Nω-nitro-l-arginine methyl ester (L-NAME)-induced intrauterine growth restriction (IUGR).. An in vivo experimental study was conducted where 40 pregnant Sprague-Dawley rats were randomly assigned to receive either: (1) control, (2) L-NAME 50 mg/kg/d by gavage (days 14 to 19), (3) L-NAME and sildenafil 15 mg/kg/d by gavage, or (4) sildenafil (days 14 to 21). On day 21, a hysterotomy was performed and all fetuses (live and dead) were counted, examined, and weighed. The primary outcome measure was the difference in pup birth weight.. The median number of live pups per dam was 11.5 (range: 1 to 15), 13.5 (2 to 17), 13.5 (7 to 16), and 11.5 (4 to 17) in controls, L-NAME, sildenafil, and combined drug groups, respectively (p = 0.02). Rats treated with L-NAME had a significantly higher number of stillbirths compared with control (p = 0.013) and sildenafil (p = 0.008) groups. L-NAME reduced pup birth weight compared with controls (4.53 ± 1.49 versus 5.65 ± 1.63 g, p < 0.001); this effect was more pronounced in the L-NAME and sildenafil groups (3.37 ± 1.25 g, p < 0.001).. Our data indicate that sildenafil citrate does not ameliorate L-NAME-induced IUGR, and in the doses utilized in this study might even have a synergistic negative effect on pup birth weight.

Topics: Animals; Birth Weight; Disease Models, Animal; Female; Fetal Growth Retardation; NG-Nitroarginine Methyl Ester; Piperazines; Pre-Eclampsia; Pregnancy; Proteinuria; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Vasodilator Agents

To evaluate perinatal outcome after sildenafil citrate (SC) administration at the onset of pregnancy in a rat pre-eclampsia model.. In vivo animal experimental study.. Fundación IVI-Instituto Universitario IVI, Valencia, Spain.. Control and pre-eclampsia-induced pregnant Wistar rats exposed to chronic SC administration.. We evaluated the use of SC, which was tested as a potential therapeutic tool to maintain vasodilatation in complicated pregnancies. We have demonstrated previously that SC shows a hypotensive selective effect in normal rat pregnancies when compared with nonpregnant animals.. Maternal blood pressure, weight and mortality during pre- and postnatal development, maternal blood cellularity and haemodynamic changes with maternal and fetal Doppler quantitative indices.. SC restores normal values of blood pressure, cell count and proteinuria for maternal syndrome. In offspring, SC improves weight gain and increases survival rates without fetotoxic effects. According to the haemodynamic results, SC has a significant effect on the resistance index in the uterine artery in pre-eclamptic animals, as it restores normal values to correlate with an increase in fetal perfusion through the ductus venosus.. These results suggest that SC administration during pregnancy may have a potential benefit for the treatment of hypertension during pregnancy by reversing the maternal effects of pre-eclampsia and by improving uteroplacental and fetal perfusion.

Topics: Animals; Blood Pressure; Female; Fetus; Phosphodiesterase 5 Inhibitors; Piperazines; Pre-Eclampsia; Pregnancy; Purines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Treatment Outcome; Ultrasonography, Doppler

To determine if the phosphodiesterase type 5 inhibitor, sildenafil citrate improves endothelial-dependent relaxation of small arteries from women with preeclampsia.. Myometrial and omental biopsies were taken from women participating in a randomized placebo-controlled trial using sildenafil citrate in women with preeclampsia. Vasoconstriction and endothelial-dependent relaxation of small arteries was measured utilizing wire myography.. Vasoconstriction and endothelial-dependent relaxation of myometrial and omental arteries were not altered in women taking sildenafil.. Acute effects may have been lost as sildenafil administration occurred many hours prior to myography. Plasma sildenafil levels may have been lower than required for vascular response.

Topics: Adult; Analysis of Variance; Arteries; Female; Humans; Myometrium; Phosphodiesterase 5 Inhibitors; Piperazines; Pre-Eclampsia; Pregnancy; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones; Vasoconstriction

We have previously shown that sildenafil citrate improves various fetal outcomes in pregnant, L-NAME treated, Sprague-Dawley rats. We therefore aimed to identify which component/s of this diverse pathophysiologic cascade is/are improved by this drug.. This study is a sub-analysis of plasma samples obtained in a previous study in which 24 pregnant Sprague-Dawley dams were divided into three groups (n=8) i.e. the control group (CON), the experimental control group (PRE) where the pre-eclampsia-like symptoms were induced using l-NAME, and the experimental group (SCT) where the pre-eclampsia-like symptoms were once again induced using L-NAME but these animals were treated with sildenafil citrate. On gestation day 20 blood samples were collected in heparin-coated tubes and plasma samples were then analysed for specific variables using commercially available kits for rats.. There was a significant increase in the plasma levels of soluble fms-like tyrosine kinase1 (sFlt-1) in the PRE group (1228.80±116.29 pg/ml) when compared to the CON (774.91±26.81 pg/ml) and SCT (698.98±20.78 pg/ml) groups, respectively (p<0.001). The plasma levels of soluble endoglin (sEng) were significantly decreased in the SCT group (149.47±3.72 ng/ml) when compared to the CON (178.52±5.33 ng/ml) and PRE (183.44±8.294 ng/ml) groups, respectively (p<0.01). Plasma nitric oxide and l-arginine levels showed a decreasing trend in the PRE groups when compared to the control (CON) and treated (SCT) groups, respectively.. Sildenafil citrate reduces the plasma levels of anti-angiogenic factors, sFlt-1 and sEng, in pre-eclamptic (L-NAME induced) Sprague-Dawley rats and may therefore be responsible for the reduction in blood pressure and proteinuria as well as the improved fetal outcomes noted in an earlier study.

Topics: Animals; Arginine; Blood Pressure; Endoglin; Female; Intracellular Signaling Peptides and Proteins; Models, Animal; NG-Nitroarginine Methyl Ester; Nitric Oxide; Piperazines; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Pregnancy, Animal; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Vascular Endothelial Growth Factor Receptor-1; Vasodilator Agents

This study aimed to investigate the effects of sildenafil citrate on various fetal and physiological parameters, including fetal mortality, number of pups, placental weights and micro-albuminuria in pregnant, L-NAME treated Sprague-Dawley rats.. Twenty-four pregnant female Sprague-Dawley rats were divided into 3 groups (n=8). In the L-NAME treated group (PRE), l-NAME (0.3 g/l, drinking water) was used to induce pre-eclampsia-like symptoms on day 1 of the experiment. The experimental group (SCT) also received L-NAME (0.3 g/l, drinking water) on day 1 of the experiment. However, sildenafil citrate (10 mg/kg, s.c., daily) was administered as the test compound from day 7 until day 19. The experimental control (CON) did not receive either L-NAME or sildenafil citrate. L-NAME administration was discontinued in both the PRE and the SCT groups on day 19 of the experiment and the animals were given access to normal drinking water ad libitum. All the animals were sacrificed on day 20, at which time a laparotomy was performed and the various fetal parameters measured. On day 0 and day 20, blood pressure measurements were recorded non-invasively and protein estimations in 24h urine samples were conducted.. Sildenafil citrate decreased fetal mortality and protein excretion and further demonstrated a trend toward increasing birth and placental weights in pregnant, L-NAME treated, Sprague-Dawley rats. In addition, sildenafil citrate administration ameliorated the amplification of the L-NAME induced hypertension in the SCT group.. We speculate that sildenafil citrate by potentiating the effects of nitric oxide in vivo improves uterine artery blood flow resulting in improved fetal outcomes in pregnant, L-NAME treated, Sprague-Dawley rats.

Topics: Analysis of Variance; Animals; Blood Pressure; Disease Models, Animal; Female; Fetal Death; NG-Nitroarginine Methyl Ester; Piperazines; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Vasodilator Agents

Topics: Female; Humans; Phosphodiesterase Inhibitors; Piperazines; Pre-Eclampsia; Pregnancy; Purines; Randomized Controlled Trials as Topic; Sildenafil Citrate; Sulfones

Pre-eclampsia is an important hypertensive pregnancy disorder and a main cause of maternal and fetal morbidity and mortality. Children born from mothers with pre-eclampsia may present cognitive deficits. The mechanisms leading to this cognitive impairment remain unclear and no treatments to improve it have been tested. Pre-eclampsia is associated with impaired regulation of the nitric oxide-3'-5'guanosine monophosphate cyclic (cGMP) pathway, which modulates some cognitive functions. We hypothesized that alterations in the NO-cGMP pathway would be involved in the mechanisms leading to cognitive impairment in rats born to pre-eclamptic mothers and that treatment with sildenafil, an inhibitor of the phosphodiesterase that degrades cGMP, could restore their cognitive function. To test these hypotheses, we used an animal model of pre-eclampsia in rats: pregnant rats treated with l-nitro-arginine methyl ester, an inhibitor of nitric oxide synthase. Using this model, we assessed: (1) whether rats born to pre-eclamptic mothers show reduced learning ability and/or altered motor activity or coordination when they are 2 months-old; (2) whether cognitive impairment is associated with reduced function of the glutamate-NO-cGMP pathway in brain in vivo; and (3) whether treatment of the mothers with sildenafil prevents this cognitive and motor alterations. The results reported show that the ability to learn a conditional discrimination task in a Y maze is reduced in rats born to pre-eclamptic mothers. This impairment was associated with reduced function of the glutamate-NO-cGMP pathway in brain in vivo, as assessed by microdialysis in freely moving rats. Treatment with sildenafil restores the function of this pathway and learning ability.

Topics: Animals; Blood Pressure; Cerebellum; Cyclic GMP; Discrimination Learning; Female; Glutamic Acid; Learning; Maze Learning; Microdialysis; Motor Activity; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Phosphodiesterase Inhibitors; Piperazines; Pre-Eclampsia; Pregnancy; Prenatal Exposure Delayed Effects; Purines; Rats; Sildenafil Citrate; Sulfones

The pathophysiology of pre-eclampsia is still unknown thus effective primary prevention is not possible at the stage. The present study was conducted to research the smooth muscle responses in the pre-eclampsia model with suramin treated rats and the effect of phosphodiesterase-5 (PDE5) inhibitor on these responses. Rats of three groups; control, suramin and suramin+sildenafil were given intraperitoneal injections of saline, suramin or sildenafil citrate. Suramin injections caused increased blood pressure, protein in urine and caused fetal growth retardation. The use of sildenafil citrate straightened significantly both blood pressure and average fetus weight, but did not reach to control values. At the end of pregnancy, thoracic aorta rings were exposed to contractile and relaxant agents. KCl contraction responses, sodium nitroprusside and papaverine relaxation responses were similar in three groups. Contraction responses of phenylephrine, increased significantly in suramin group. Relaxation responses of acethylcholine and bradykinin decreased in suramin group. The use of sildenafil citrate partially straightened both relaxation and contraction responses, but did not reach to control values. In all groups in the presence of L-nitromonomethylarginine (L-NAME), 1H-(1, 2, 4) oxadiazole (4, 3-a) guinoxalin-1-one (ODQ) and indomethacin decreased the relaxation responses of acetylcholine and bradykinin. The cyclic guanosine monophosphate (cGMP) content of thoracic aorta tissue was determined by radioimmunoassay technique. The content of cGMP in suramin group decreased and use of sildenafil citrate increased the cGMP content but did not reach to control values. We conclude that in pre-eclampsia, the increase of contraction responses, the decrease of relaxation responses and the decrease of cGMP content can depend on insufficiency about synthesis or release of relaxant factors which was released from the vessel endothelium. The results in this study show that in pre-eclampsia; PDE5 inhibitors enhance endothelial function and may be used for protection. Further studies are needed to clear the efficiency and safety of PDE5 inhibitors.

Topics: Animals; Aorta, Thoracic; Blood Pressure; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelium, Vascular; Female; Fetal Development; Fetal Growth Retardation; Muscle, Smooth, Vascular; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Pre-Eclampsia; Pregnancy; Proteinuria; Purines; Radioimmunoassay; Rats; Sildenafil Citrate; Sulfones; Suramin; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

In pre-eclampsia (PE), endothelium-dependent function of myometrial small arteries is markedly attenuated. The residual PE response is wholly NO mediated. We have previously demonstrated that PDE5 inhibition can improve endothelial function in myometrial small arteries from women with PE. We aimed to assess whether the effect of PDE5 inhibition in PE was myometrial artery specific.. Small arteries were dissected from omental biopsies obtained at Caesarean section from normal pregnant women (NP, N = 20) and women with PE (N = 11). Chorionic plate small arteries were dissected from NP (N = 13) and PE (N = 11) placentae. Vasoconstriction (arginine vasopressin or thromboxane-mimetic U46619) and endothelial-dependent relaxation were assessed by wire and pressure myography. Constriction/relaxation curves were repeated post 1h incubation with PDE5 inhibitors UK-343664 or sildenafil citrate (0, 10 or 100 nM).. Omental artery constriction was increased in PE. Omental vessel constriction was unaffected by PDE5 inhibition. Sildenafil citrate improved bradykinin-induced but not acetylcholine-induced relaxation of omental small arteries from NP women. PDE5 inhibition did not alter relaxation of omental arteries from women with PE. Placental small arteries were unaffected by PDE5 inhibition.. Use of PDE5 inhibitors does not significantly alter endothelial-dependent relaxation in omental or placental small arteries from PE women.

Topics: Analysis of Variance; Arterioles; Biopsy; Case-Control Studies; Endothelium, Vascular; Female; Humans; Myography; Myometrium; Omentum; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Placenta; Pre-Eclampsia; Pregnancy; Purines; Pyrimidinones; Sildenafil Citrate; Sulfones; Treatment Outcome; Uterine Contraction; Vasodilation; Vasodilator Agents