cyclic-gmp and Pre-Eclampsia

The present study intends to review the possibility of using phosphodiesterase inhibitors as a treatment option for preeclampsia, addressing potential risks and benefits.. Preeclampsia is the most common hypertensive disorder of pregnancy, often responsible for severe maternal and fetal complications, which can lead to early pregnancy termination and death. Despite the numerous studies, its pathophysiology is still unclear, although it seems to involve a multiplicity of complex factors related to angiogenesis, ineffective vasodilation, oxidative stress, inflammatory cytokines, and endothelial dysfunction. It has been hypothetically suggested that the use of phosphodiesterase inhibitors is capable of improving placental and fetal perfusion, contributing to gestational scenario, by decreasing the symptomatology and severity of this syndrome. In this literature review, it has been found that most of the studies were conducted in animal models, and there is still lack of evidence supporting its use in clinical practice. Research in human indicates conflicting findings; randomized controlled trials were scarce and did not demonstrate any benefit in morbidity or mortality. Data regarding to pathophysiological and interventional research are described and commented in this review. The use of phosphodiesterase inhibitors in the treatment of preeclampsia is controversial and should not be encouraged taking into account recent data.

Topics: Animals; Cyclic GMP; Disease Models, Animal; Female; Humans; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Pre-Eclampsia; Pregnancy; Vasodilation

Preeclampsia is an autoimmune disorder characterized by hypertension. It begins with abnormal cytotrophoblast apoptosis, which leads to inflammation and an increase in the levels of anti-angiogenic factors followed by the disruption of the angiogenic status. Increased levels of fetal DNA and RNA coming from the placenta, one of the most commonly affected organs in pregnancies complicated by preeclampsia, have been found in pregnant women with the condition. However, it remains unknown as to whether this is a cause or a consequence of preeclampsia. Few studies have been carried out on preeclampsia in which an animal model of preeclampsia was induced by an injection of different types of DNA that are mimic fetal DNA and provoke inflammation through Toll-like receptor 9 (TLR9) or cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). The specific mechanisms involved in the development of preeclampsia are not yet fully understood. It is hypothesized that the presence of different fragments of fetal DNA in maternal plasma may cause for the development of preeclampsia. The function of DNase during preeclampsia also remains unresolved. Studies have suggested that its activity is decreased or the DNA is protected against its effects. Further research is required to uncover the pathogenesis of preeclampsia and focus more on the condition of patients with the condition.

Topics: Animals; Cyclic GMP; Disease Models, Animal; DNA; Female; Fetus; Humans; Inflammation; Pre-Eclampsia; Pregnancy; RNA; Toll-Like Receptor 9

Topics: Asphyxia Neonatorum; Biomarkers; Blood Circulation; Cyclic GMP; Female; Fetal Diseases; Fetal Growth Retardation; Guanylate Cyclase; Humans; Hypoxia; Infant, Newborn; Natriuretic Peptides; Pre-Eclampsia; Pregnancy; Receptors, Atrial Natriuretic Factor; Uterine Contraction; Uterus

Pregnancy-induced hypertension (PIH) remains a common cause of maternal and fetal morbidity and mortality. During the past 7 years, some progress has been made in the prevention of PIH. Specifically, clinical studies have shown that supplementation with calcium can significantly reduce the frequency of PIH, especially in populations with a low calcium intake. We have suggested that, in such a population, calcium supplementation is a safe and effective measure for reducing the incidence of PIH. Calcium supplementation reduces the risk of PIH by maintaining the serum ionized calcium level which is crucial for the production of endothelial nitric oxide, the increased generation of which maintains the vasodilatation that is characteristic of normal pregnancy. In PIH there is an impaired nitric oxide synthesis and cyclic GMP production.

Topics: Arginine; Calcium; Cyclic GMP; Female; Food, Fortified; Hemodynamics; Homeostasis; Humans; Hypertension; Nitric Oxide; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular

Topics: Adult; Amniocentesis; Amniotic Fluid; Cyclic GMP; Female; Humans; Pre-Eclampsia; Pregnancy

Recently pentoxifylline, a non-selective phosphodiesterase inhibitor and adenosine receptor antagonist, has attracted much interest for the treatment of the increased vascular resistance and endothelial dysfunction in pre-eclampsia. We therefore investigated the placental transfer, vascular effects and anti-inflammatory actions of pentoxifylline in healthy and pre-eclamptic human placentas.. The placental transfer and metabolism of pentoxifylline were studied using ex vivo placenta perfusion experiments. In wire myography experiments with chorionic plate arteries, pentoxifyllines vasodilator properties were investigated, focusing on the cGMP and cAMP pathways and adenosine receptors. Its effects on inflammatory factors were also studied in placental explants.. Pentoxifylline transferred from the maternal to foetal circulation, reaching identical concentrations. The placenta metabolized pentoxifylline into its active metabolite lisofylline (M1), which was released into both circulations. In healthy placentas, pentoxifylline potentiated cAMP- and cGMP-induced vasodilation, as well as causing vasodilation by adenosine A. Pentoxifylline is transferred across and metabolized by the placenta. Its beneficial effects on the NO pathway and inflammation are not retained in pre-eclampsia, limiting its application in this disease, although it could be useful for other placenta-related disorders. Future studies might focus on selective A

Topics: Adenosine; Anti-Inflammatory Agents; Cyclic GMP; Female; Humans; Nitric Oxide Synthase; Pentoxifylline; Phosphodiesterase Inhibitors; Placenta; Pre-Eclampsia; Pregnancy; Purinergic P1 Receptor Antagonists; Vasodilator Agents

The Reduced Uterine Perfusion Pressure (RUPP) rat model of placental ischemia recapitulates many characteristics of preeclampsia including maternal hypertension, intrauterine growth restriction (IUGR), and increased cytolytic natural killer cells (cNKs). While we have previously shown a 5-fold higher cytotoxicity of RUPP NKs versus normal pregnant NKs, their role in RUPP pathophysiology remains unclear. In this study, we tested the hypotheses that (1) adoptive transfer of RUPP-stimulated NKs will induce maternal hypertension and IUGR in normal pregnant control (Sham) rats and (2) adoptive transfer of Sham NKs will attenuate maternal hypertension and IUGR in RUPP rats.. On gestation day (GD)14, vehicle or 5 × 10. Adoptive transfer of RUPP NKs into Sham rats resulted in elevated NK activation, UARI, placental oxidative stress, and preproendothelin expression as well as reduced circulating nitrate/nitrite. This led to maternal hypertension and IUGR. RUPP recipients of Sham NKs demonstrated normalized NK activation, sFlt-1, circulating and placental VEGF, and UARI, which led to improved maternal blood pressure and normal fetal growth.. These data suggest a direct role for cNKs in causing preeclampsia pathophysiology and a role for normal NKs to improve maternal outcomes and IUGR during late gestation.

Topics: Adoptive Transfer; Animals; Cyclic GMP; Cytokines; Female; Fetal Growth Retardation; Ischemia; Killer Cells, Natural; Nitrates; Nitric Oxide Synthase Type III; Nitrites; Oxidative Stress; Phenotype; Placenta; Pre-Eclampsia; Pregnancy; Rats, Sprague-Dawley; Reactive Oxygen Species; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

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

We investigated the efficacy and mechanisms of tadalafil, a selective phosphodiesterase 5 inhibitor, in treating preeclampsia (PE) with fetal growth restriction (FGR) using L-NG-nitroarginine methyl ester (L-NAME)-induced PE with FGR in pregnant mice as our experimental model.. C57BL/6 mice were divided into 2 groups 11 days postcoitum (d.p.c.). A control group of dams (C dam) received 0.5% carboxymethylcellulose (CMC). A L-NAME-treated group received 1 mg/ml L-NAME dissolved in CMC. The L-NAME-treated dams were divided into 2 subgroups 13 d.p.c. One subgroup continued to receive L-NAME (L dams). The other subgroup received L-NAME with 0.08 mg/ml tadalafil suspended in CMC (TL dams). Maternal systolic blood pressure (SBP) and proteinuria were assessed 16 d.p.c. Fetal weight was recorded, and placentas and maternal kidneys were collected 17 d.p.c.. Maternal SBP, proteinuria, and fetal weight were improved for TL dams compared to L dams. The placental concentration of placental growth factor (PlGF) was higher for TL dams than for the C and L dams. The placental maternal blood sinuses of L dams were narrower than those of C dams, but those of TL dams improved to a similar width as C dams. Glomerular oxidative stress was ameliorated in TL dams compared to L dams.. Tadalafil dilates the placental maternal blood sinuses, which leads to increase PlGF production, and contributes to facilitate fetal growth and improve maternal SBP. Moreover, tadalafil ameliorates glomerular damage by reducing oxidative stress. These results suggest that tadalafil is a candidate for treatment of PE with FGR.

Topics: Animals; Blood Pressure; Cyclic GMP; Enzyme Inhibitors; Female; Fetal Development; Fetal Growth Retardation; Kidney; Mice; Mice, Inbred C57BL; NG-Nitroarginine Methyl Ester; Oxidative Stress; Phosphodiesterase 5 Inhibitors; Placenta; Pre-Eclampsia; Pregnancy; Proteinuria; Tadalafil

Placental vascular dysfunction was suggested to be critical for placental ischemia-initiated hypertension in preeclampsia, although the contributions of endothelium involved are unclear. The present study found, unlike non-placental vessels, acetylcholine showed no vasodilatation effect on placental vessels, indicating that endothelial-derived nitric oxide (NO) was extremely weak in placental vessels. Placental vascular responses to exogenous NO from sodium nitroprusside (SNP) were significantly different from non-placental vessels. These results were further confirmed in sheep, and rat vessels. In preeclamptic placental vessels, acetylcholine also showed no vasodilatation effects, while vascular responses to SNP were suppressed, associated with impaired cGMP/sGC pathway in vascular smooth muscle cells (VSMCs). The current theory on placental ischemia-initiated hypertension in preeclampsia focused on changes in placental vascular functions, including endothelial dysfunction. This study found the placental endothelium contributed very poorly to vasodilatation, and altered vascular functions in preeclampsia mainly occurred in VSMCs instead of endothelial cells. The findings contribute importantly to understanding the special feature of placental vascular functions and its pathophysiological changes in the development of hypertension in preeclampsia.

Topics: Animals; Blood Pressure; Case-Control Studies; Cyclic GMP; Dose-Response Relationship, Drug; Endothelium, Vascular; Female; Humans; In Vitro Techniques; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nitric Oxide; Placenta; Pre-Eclampsia; Pregnancy; Rats, Sprague-Dawley; Sheep, Domestic; Soluble Guanylyl Cyclase; Umbilical Arteries; Umbilical Veins; Vasodilation; Vasodilator Agents

Topics: Cyclic GMP; Female; Humans; Platelet Activation; Pre-Eclampsia; Pregnancy

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

The present study was designed to investigate the effects of YC-1, a nitric oxide (NO)-independent soluble guanylate cyclase (sGC) activator, and DEA/NO, a NO donor, on smooth muscle responses in the preeclampsia model with suramin-treated rats and on the levels of cyclic guanosine monophosphate (cGMP) of thoracic aorta rings isolated from term-pregnant rats. Rats of 2 groups, control group and suramin group, were given intraperitoneal injection of saline or suramin, respectively. Suramin injection caused increased blood pressure, protein in urine, and fetal growth retardation. Thoracic aorta rings were exposed to contractile and relaxant agents. KCl contraction and papaverine relaxation responses were similar. Relaxation responses of YC-1 and DEA/NO decreased in suramin group. In both groups in the presence of ODQ, a sGC inhibitor, the relaxation responses of YC-1 and DEA/NO decreased. The cGMP content was determined by radioimmunoassay technique. The content of cGMP in the suramin group decreased. In the presence of YC-1 and DEA/NO in both groups, cGMP content increased, but in ODQ-added groups, there was a significant decrease. We conclude that in preeclampsia, the decrease of relaxation responses and the decrease of cGMP content could be due to the reduction in stimulation of sGC and the decrease in cGMP levels.

Topics: Animals; Aorta, Thoracic; Blood Pressure; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Activators; Enzyme Inhibitors; Female; Fetal Growth Retardation; Guanylate Cyclase; Indazoles; Muscle, Smooth, Vascular; Nitric Oxide; Nitric Oxide Donors; Pre-Eclampsia; Pregnancy; Proteinuria; Quaternary Ammonium Compounds; Rats; Rats, Wistar; Second Messenger Systems; Suramin; Vasodilation; Vasodilator Agents

There may be a relationship between endothelial dysfunction, coagulation activation and nitric oxide (NO) synthesis in women with mild and severe preeclampsia (PE).. Plasma thrombomodulin (TM), D-Dimer (D-Di), cyclic guanosine monophosphate (cGMP) and placental nitric oxide synthase activity (NOS) were investigated in 21 normotensive pregnant women (G1), 22 pregnant women with mild PE (G2) and 20 pregnant women with severe PE (G3).. TM and D-Di were significantly increased in G3 compared to G1 (P=0.001 and P=0.006, respectively) and G2 (P=0.001, in both cases). However, there was no significant difference when G1 was compared to G2. For total NOS, calcium independent NOS, calcium dependent NOS no significant difference was observed among the groups studied.. TM and D-Di levels are raised in women with severe PE compared to normotensive pregnant women and women with mild PE. While increased TM levels may reflect endothelial dysfunction, raised D-Di levels indicate a hypercoagulable state. NO assessed by 2 indirect methods did not show any significant difference among the groups studied. Due to current limitations with in vitro NO measurements and interferences associated with NO bioavailability, particularly in PE, such findings should not be over-interpreted.

Topics: Adult; Blood Coagulation; Cyclic GMP; Endothelial Cells; Female; Fibrin Fibrinogen Degradation Products; Humans; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Placenta; Pre-Eclampsia; Pregnancy; Severity of Illness Index; Thrombomodulin

Preeclampsia (PE) is a major cause of fetal growth restriction and perinatal mortality, which involves oxidative stress and vasodilator signaling disorder. S-allyl-L-cysteine (SAC) is one of the most abundant compounds in garlic extracts, and possesses several biological activities. This research was designed to investigate the protective effects of SAC against H(2)O(2)-induced oxidative insults, as well as the effects on NO/cGMP signaling pathway in placenta. We used TEV-1 cells and placental explants to detect the effects of SAC. TEV-1 cells and human placental explants were separately exposed to SAC, H(2)O(2), or a combination of H(2)O(2) and SAC. Intracellular ROS was detected by flow cytometry; the NO level was detected by an NO metabolites (NOx) assay; the cGMP level was simultaneously measured by the method of radioimmunoassay; the expression of eNOS in TEV-1 cells was measured by immunochemistry and Western blot. Our findings showed that H(2)O(2) treatment increased ROS productions in TEV-1 cells and significantly decreased cGMP and NO level either in TEV-1 cells or explants compared to the control groups (p < 0.05). The expression of eNOS in TEV-1 cells also significantly decreased in H(2)O(2) treated group compared to the control group (p < 0.05). Co-treatment of H(2)O(2) and SAC significantly decreased ROS productions, and increased NO, cGMP and eNOS level compared to the H(2)O(2) treated alone groups (p < 0.05), which were all reverted back to near control levels. Further more, SAC treatment increased NO and cGMP level of TEV-1 cells and explants in a dose-dependent manner even at non-oxidative stress status (p < 0.05). However, when the TEV-1 cells were cultured in the presence of NOS inhibitor (L-NAME) and NO donor (SNP), additional SAC treatment still significantly increased the NO level in comparison with SAC non-treated group (p < 0.05). In conclusion, these results demonstrate that ROS (H(2)O(2)-mediated) can induce insults to NO/cGMP pathway, while SAC could antagonize this insult. And SAC also possesses the ability to increase NO and cGMP level at non-oxidative stress status in TEV-1 cells and placenta explants. SAC is therefore hypothesized to be a potential drug for PE treatment.

Topics: Cell Line; Cyclic GMP; Cysteine; Female; Humans; Hydrogen Peroxide; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidative Stress; Placenta; Pre-Eclampsia; Pregnancy

We compared nitrite, B-type natriuretic peptide (BNP), and cGMP levels in preeclamptic with those found in healthy pregnant.. We studied 21 healthy pregnant and 27 preeclamptic. Plasma cGMP and BNP levels were determined by ELISA. Nitrite levels were determined by chemiluminescence.. Higher cGMP and BNP, and lower nitrite levels were found in preeclamptic versus healthy pregnant.. Altered cGMP levels reflect increased BNP levels and not impaired nitric oxide activity in preeclampsia.

Topics: Adult; Blood Pressure; Case-Control Studies; Cyclic GMP; Female; Humans; Infant, Low Birth Weight; Infant, Newborn; Natriuretic Peptide, Brain; Nitric Oxide; Nitrites; Pre-Eclampsia; Pregnancy; Reference Values; Young Adult

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

Defective nitric oxide (NO)-mediated vasodilation is widely regarded as an underlying cause of hypertension in pre-eclampsia, although there are also arguments against this hypothesis.. We examined both the mRNA levels and the presence of a Glu298Asp substitution in the NO synthase (NOS) gene, as well as the NO metabolite concentration, in placentas and maternal sera from women with pre-eclampsia and in normotensive pregnant controls (25-40 vs. 24-41 weeks of gestation).. Pre-eclamptic and control placentas did not show any significant differences in their NO metabolite levels or their NOS expression levels as measured by quantitative RT-PCR. In addition, we did not find any association between pre-eclampsia and the occurrence of the Glu298Asp amino acid substitution in the NOS gene. In contrast, high maternal circulating NO metabolites were evident in severe pre-eclampsia (p < 0.0001). Although a positive correlation between circulating NO metabolites and blood pressure was not observed, uterine artery resistance measured by ultrasound was found to positively correlate with the maternal NO levels.. Our current data suggest that an altered placental NOS pathway is unlikely to be the primary cause of pre-eclampsia and that the activation of this pathway is possibly in response to maternal symptoms.

Topics: Adult; Aspartic Acid; Case-Control Studies; Cyclic GMP; Female; Gestational Age; Glutamic Acid; Humans; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Placenta; Polymorphism, Single Nucleotide; Pre-Eclampsia; Pregnancy; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

A number of biochemical parameters (total nitrites and nitrates (NO(x)), cyclic guanosine monophosphate (cGMP), nitrotyrosine, medium-weight molecules (MCM) in the placenta were determined in women with gestosis during discoordinated and powerless labor. Thirty placentas (10 placentas from parturients after discoordinated labor, 10 from those after powerless labor, 10 placentas as a control group) were examined. Changes in the parameters under study were found to result in the development of nitroxide and oxidant stresses and endotoxicosis. The biochemical parameters should be considered as placental criteria for the differential diagnosis of labor anomalies in gestosis, such as powerless and discoordinated labors.

Topics: Adult; Cyclic GMP; Female; Humans; Nitrates; Nitrites; Obstetric Labor Complications; Oxidative Stress; Placenta; Pre-Eclampsia; Pregnancy

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

Topics: Cyclic GMP; Female; Humans; Nitric Oxide; Pre-Eclampsia; Pregnancy

The gestational hypertension -HG- and preeclampsia -P- are hypertensive diseases whose pathogenic mechanism has not been determined yet. The aim of this work is to define some patterns of vasoactive factors release that allow to explain the origin of the differences between both entities.. Prospective case-control study.. Two groups of target patients were consecutively selected, GH (n=21) and P patients (n=21). Every patient was matched with a pregnant of similar age and week of pregnancy. Two control groups were obtained, one respect to the GH and another one respect to the P group. A biochemistry, blood cell count, coagulation and quantification of vasoactive factors endothelin, nitrites and GMPc were performed in every woman. Results of GH and P groups were compared with their respective control group with the paired Student's t Test.. Both systolic and diastolic arterial pressures were higher in hypertensive pregnants (GH and P) than in their respective controls. Moreover, blood endothelin and GMPc were higher in GH and P. GH pregnants showed decreased norepinephrine and increased epinephrine urinary excretion , as well as an increased plasma nitrites concentration than control group. P patients did not show statistically significant differences in catecholamines urinary excretion nor in plasma nitrites concentration respect their control group.. There are relevant differences in the synthesis patterns of vasoactive factors between gestational hypertension and preeclampsia. These differences could account for a decreased tissue perfusion in preeclampsia and could also contribute to the genesis of the renal dysfunction of this entity.

Topics: Adult; Case-Control Studies; Catecholamines; Cyclic GMP; Endothelins; Female; Humans; Hypertension, Pregnancy-Induced; Nitrites; Pre-Eclampsia; Pregnancy; Prospective Studies; Renal Insufficiency

The Nitric Oxide (NO) system plays an important role in the establishment and maintenance of the feto-placental circulation. Research on the pathogenesis of preeclampsia in several studies has established the involvement of the NO-system in preeclampsia and fetal intrauterine growth restriction (IUGR). In the presented study we analyzed the urine and plasma concentrations of nitrite/nitrate, the stable endproducts of NO and its second messenger, cyclic Guanosinemonophosphate (cGMP) in normal, preeclamptic and IUGR pregnancies.. In total 76 patients were investigated in a prospective study for repeated determination of plasma and urinary levels of nitrate/nitrite and cGMP: 49 patients with a normal course of pregnancy, 14 patients with fetal IUGR and 13 patients with preeclampsia were included into the study. Plasma and urine Nitrite/Nitrate-concentrations were determined using a Colorimetric Assay (Cayman Inc., USA), concentrations of the second messenger cGMP in plasma and urinary samples were determined with a J(125)-Radio-Immuno-Assay (ibl Inc., Germany). The Stat View Program (Abacus Concepts, Inc., Berkeley, CA, 1992-1998) was used for statistical analysis, a P value <0.05 was considered significant.. Analyzing the data with the Kruskall-Wallis test a significance was reached for Plasma Nitrite/Nitrate (P=0.0236), plasma cGMP (P=0.004) and urinary nitrite/nitrate (P=0.032). No significance was seen for urinary cGMP (P=0.656). Comparing normal and preeclamptic and normal and IUGR pregnancies the following significant differences were seen (Mann-Whitney U test): In preeclamptic pregnancies urine nitrite/nitrate concentration was significantly lower compared to normal pregnancies (P=0.009) No significant difference between normal and preeclamptic pregnancies for plasma nitrite/nitrate (P=0.819) and plasma-cGMP (P=0.072) could be observed. In IUGR pregnancies plasma nitrite/nitrate and the plasma-cGMP concentrations were both significantly lower compared to normal pregnancies (P=0.0077 and 0.0066) in IUGR-pregnancies. No significance was reached when analyzing urine-Nitrite/Nitrate (P=0.7).. Whereas in preeclampsia a reduced urinary nitrite/nitrate was analyzed, IUGR pregnancies showed reduced plasma nitrite/nitrate and cGMP. A reduced release of NO into the maternal circulation might lead to the presented findings and be involved in the pathogenesis of preeclampsia and fetal IUGR.

Topics: Birth Weight; Cyclic GMP; Female; Fetal Growth Retardation; Humans; Infant, Newborn; Nitrates; Nitric Oxide; Nitrites; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Prospective Studies

Our aim was to determine the reduced function of endothelial nitric oxide in preeclampsia by use of noninvasive techniques in vivo.. With the use of a high-resolution ultrasound transducer, diameters of brachial artery were measured after reactive hyperemia in 20 nonpregnant women, 20 normotensive pregnant women, and 15 women with preeclampsia. The concentrations of cyclic guanosine monophosphate were measured in samples of platelets from all groups.. Flow-mediated vasodilation at 1 minute after deflation was higher in the normotensive pregnant women (115.1% +/- 6.5%) than in the nonpregnant women (108.7% +/- 3.9%); flow-mediated vasodilation was lower in women with preeclampsia (106.8% +/- 2.7%) than in the normotensive pregnant women. The concentration of platelet cyclic guanosine monophosphate was higher in the normotensive pregnant women than in the nonpregnant women (2.21 +/- 1.10 pmol/mL/10(8) cells vs 0.746 +/- 0.381 pmol/mL/10(8) cells). There was no difference between the normotensive pregnant and the preeclamptic group (2.81 +/- 1.82 pmol/mL/10(8) cells). Furthermore, the increase in cyclic guanosine monophosphate by sodium nitroprusside in platelet samples that were obtained from the normotensive pregnant women was larger than the samples from the nonpregnant women (6.20 +/- 4.2 pmol/mL/10(8) cells vs 1.62 +/- 0.81 pmol/mL/10(8) cells). The increase in cyclic guanosine monophosphate from the women with preeclampsia did not differ from that in the normotensive pregnant women (5.84 +/- 3.73 pmol/ml/10(8) cells).. These results indicate that reduced endothelial nitric oxide activity might be due to a reduction of nitric oxide-cyclic guanosine monophosphate activity rather than its production in preeclampsia.

Topics: Adult; Cyclic GMP; Endothelium, Vascular; Female; Humans; Nitric Oxide; Pre-Eclampsia; Pregnancy; Regional Blood Flow; Vasodilation

During pregnancy, CRH and CRH-related peptides appear to regulate the fetoplacental circulation via activation of the nitric oxide (NO)/cGMP pathway. Pregnancies with abnormal placental function such as preeclampsia (PE) are characterized by increased maternal plasma CRH concentrations and reduced placental CRH-receptor 1alpha (CRH-R1alpha) expression. In this study, we investigated the actions of CRH/CRH-related peptides on the NO/cGMP system in normal and PE placentas (n = 8 for each group). Fluorescent in situ hybridization, RT-PCR, and immunofluorescence experiments in human term placenta detected mRNAs expression for both R1 and R2 types of CRH-R, as well as urocortin (UCN) II and UCN III and showed CRH-R protein expression mainly in syncytiotrophoblast, whereas the endothelial NO synthase (eNOS) expression was confined within the cytoplasm of the chorionic villi. In placental explants, CRH and UCN induced mRNA and protein expression of eNOS, but not inducible NOS, and also caused an acute increase in cGMP levels (maximal stimulation, 80-90% above basal; P < 0.05). UCN II also induced a modest induction of cGMP (42% above basal; P < 0.05). These responses were attenuated by the NOS and soluble guanylyl cyclase inhibitors, l-N(G)-nitro-l-arginine methyl ester and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. In PE placental explants there was a significant reduction in CRH/CRH-related peptide-induced cGMP response; however, changes in the mRNA content of eNOS, inducible NOS, and soluble guanylyl cyclase (assessed by quantitative RT-PCR) between normal and PE placentas were not altered. In conclusion, we demonstrated that CRH and CRH-related peptides can positively regulate the placental NO/cGMP system. This pathway appears to be impaired in PE and may contribute toward dysregulation of the balance controlling vascular resistance.

Topics: Adolescent; Adult; Birth Weight; Blood Pressure; Cesarean Section; Corticotropin-Releasing Hormone; Cyclic GMP; Female; Humans; Infant, Newborn; Nitric Oxide; Parity; Peptides; Placenta; Pre-Eclampsia; Pregnancy; Receptors, Corticotropin-Releasing Hormone; Reverse Transcriptase Polymerase Chain Reaction

To compare serum levels of nitric oxide (NO) and endothelin-1 (ET-1), and urinary concentrations of NO and cyclic guanosine monophosphate (cGMP) between preeclamptic and normotensive pregnant women.. Ninety-one preeclamptic (48 mild, 43 severe) and forty healthy normotensive pregnant women above 32 gestational weeks were recruited into study. Chemiluminesence technique was used for measuring plasma and urinary NO levels, and radioimmunoassay was used to determine plasma ET-1 and urinary cGMP levels.. Plasma and urinary NO, and urinary cGMP levels were significantly lower in preeclamptics than in the control group (respectively, p< 0.001, p< 0.001, p< 0.01). Plasma ET-1 levels were significantly higher in the preeclamptics than in the control group (p<0.001). There were significant negative correlations between plasma ET-1, plasma NO and urinary NO and cGMP in all groups. There were positive correlations between plasma NO, urinary NO and cGMP in all groups.. The imbalance between NO and ET-1 may play a significant role in the pathophysiology of preeclampsia.

Topics: Adult; Case-Control Studies; Cyclic GMP; Endothelin-1; Female; Gestational Age; Humans; Luminescent Measurements; Nitric Oxide; Pre-Eclampsia; Pregnancy; Radioimmunoassay; Regression Analysis; Severity of Illness Index

To investigate the intraplatelet cyclic guanosine-3',5'-monophosphate (cGMP) levels during normal pregnancy and preeclampsia.. Pregnant women (n = 15), women with preeclampsia (n = 15), and nonpregnant, normotensive women (n = 15) were included. Intraplatelet cyclic guanosine-3',5'-monophosphate levels were measured by an enzyme-linked immunosorbent assay.. Intraplatelet cGMP levels were significantly different among all groups (p < 0.02). The values were higher in normal pregnant women (mean 19.8 SD 2.6 fmol/10(5) platelets) in comparison to nonpregnant women (mean 7.6 SD 0.3 fmol/10(5)platelets; p = 0.001) and women with preeclampsia (mean 11.3 SD 1.8 fmol/10(5) platelets; p = 0.05). Plasma nitric oxide levels did not reveal differences between all groups.. The results of this study in a high-risk Andean population demonstrated that intraplatelet cyclic guanosine-3',5'-monophosphate levels are decreased during preeclampsia compared to normal pregnancy, suggesting a lack in action of nitric oxide.

Topics: Adult; Blood Platelets; Cyclic GMP; Female; Humans; Nitric Oxide; Pre-Eclampsia; Pregnancy

To investigate whether decidual endothelial cells (DEC) contribute to the pathogenesis of preeclampsia through abnormal nitric oxide production. Decidual endothelial cells from normal (NDEC) and preeclamptic (PEDEC) pregnancies, and also human umbilical vein endothelial cells (HUVEC), were examined.. HUVEC, NDEC, and PEDEC were incubated for 45 min in serum-free media with the addition of potential stimulators [calcium ionophore (A23187), sepiapterin, and a combination of cytokines (TNF-alpha, gamma-IFN and LPS)], and the competitive inhibitor, NG-monomethyl-L-arginine (L-NMMA). These were added alone or in combination. Supernatants were measured for nitrate/nitrite (NOx) levels and the cells acid-extracted for measurement of cyclic guanosine monophosphate (cGMP). The effect of 30 min of shear stress (approximately 20 dynes/cm2) on NO and cGMP production by NDEC and PEDEC and on production of prostacyclin and thromboxane A2, was assessed.. PEDEC and HUVEC both produced more NO than NDEC under all conditions examined. Cell-associated cGMP levels, however, were not different among the cell groups but were increased by A23187 and inhibited by L-NMMA. In control conditions, shear stress stimulated cGMP levels 5-fold (p<0.01) in both NDEC and PEDEC, and PGI2 production 2-fold (p<0.05).. DEC from preeclamptic women do not have reduced NO production and respond normally to shear stress by increasing cGMP and PGI2 production. Our results are consistent with other reports of equal or higher NO levels in preeclampsia and indicate that reduced NO production by endothelial cells is not the explanation for the vasoconstriction of uterine vessels.

Topics: Adult; Calcimycin; Case-Control Studies; Cells, Cultured; Cyclic GMP; Cytokines; Decidua; Endothelium, Vascular; Epoprostenol; Female; Humans; Nitric Oxide; omega-N-Methylarginine; Pre-Eclampsia; Pregnancy; Pteridines; Pterins; Thromboxane A2; Umbilical Veins

Preeclampsia (PE) is a leading cause of maternal hypertension in pregnancy, fetal growth restriction, premature birth, and fetal and maternal mortality (1). Activation and dysfunction of the maternal and fetal endothelium in PE may be the consequence of increased oxidative stress associated with circulating lipid peroxides (2-4), and in cases of severe maternal hypertension, uterine and umbilical artery waveforms are abnormal (5). We have investigated PE-associated abnormalities in the regulation of intracellular Ca2+ ([Ca2+]i) and cyclic guanosine monophosphate (cGMP) production (index of nitric oxide [NO]) in human fetal umbilical vein endothelial cells. Basal [Ca2+]i was slightly elevated in PE cells, whereas agonist-stimulated Ca2+ entry was reduced in cells from PE compared with normal term or age-matched preterm pregnancies. Furthermore, PE cells exhibited a decreased permeability to Ba2+ but an increased permeability to Mn2+ and Gd3+, suggesting that PE is associated with phenotypic alterations in fetal endothelial cation channel(s). Basal and histamine-stimulated cGMP levels were elevated in PE compared with preterm or normal cells, implying an increased NO production in PE. However, immunoblots for endothelial NO synthase (eNOS) and soluble guanylyl cyclase (sGC) revealed reduced eNOS expression in PE and preterm cells, with negligible changes in sGC levels. This study provides important and novel insights into abnormalities of fetal endothelial cells isolated from women with PE, reveal ing an altered cation membrane permeability and activity of eNOS-sGC pathway. As these changes are sustained in culture in vitro, this may reflect long-term "programming" of the fetal cardiovascular system.

Topics: Calcium; Cell Membrane Permeability; Cells, Cultured; Cyclic GMP; Endothelium, Vascular; Female; Fetus; Histamine; Humans; Ion Transport; Metals; Models, Biological; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Pre-Eclampsia; Pregnancy; Umbilical Veins

The objective of this study is to compare the serum levels of fibronectin, nitric oxide (NO), cyclic guanosine-monophosphate, endothelin-1, and 6-keto-prostaglandin-F 1alpha in women with and without preeclampsia before and after delivery.. We studied 20 singleton pregnancies complicated by preeclampsia, and 20 women undergoing elective cesarean delivery were selected as controls. The normalization of circulating concentrations of maternal plasma NO, cyclic guanosine-monophosphate, fibronectin, endothelin-1, thromboxane-B 2 and renin, and urinary 6-keto-prostaglandin-F 1alpha after delivery was evaluated.. Mean systolic and diastolic blood pressure (BP) in the puerperium of preeclamptic women remained high after discharge from hospital, and only circulating fibronectin levels were found to be elevated in affected women at the end of hospital stay 5 days after delivery. Normalization of the imbalance in vasoactive substances and renal impairment in preeclampsia occur more rapidly than the patient's clinical recovery, within 2-3 days postpartum.. Slow normalization of circulating fibronectin concentrations reflects slow recovery of endothelial damage in preeclampsia, which may play a major role in maintaining high BP in the puerperium. Plasma levels of endothelin-1 declined to normal levels by the third postpartum day and the finding is consistent with the hypothesis that endothelin-1 is not the major vasoconstrictor in the pathophysiology of preeclampsia.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Biomarkers; Cesarean Section; Cyclic GMP; Endothelin-1; Endothelium, Vascular; Female; Fibronectins; Humans; Longitudinal Studies; Nitric Oxide; Postpartum Period; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Time Factors; Vasoconstrictor Agents; Vasodilator Agents

Preeclampsia and fetal growth restriction are associated with poor placental perfusion, which may be accompanied by a compensatory release of vasoactive substances in the fetoplacental circuit. This study examines the effects of preeclampsia and fetal growth restriction on nitric oxide and prostacyclin signaling pathways in fetal endothelial cells.. Human umbilical vein endothelial cells from 30 control pregnancies, 18 pregnancies with preeclampsia, and 9 pregnancies with intrauterine growth restriction were cultured. Intracellular cyclic guanosine monophosphate accumulation and 6-keto-prostaglandin F1alpha production were determined.. Intracellular accumulation of cyclic guanosine monophosphate was significantly higher in the preeclampsia group and lower in the growth restriction group than in the control group (9.8, 1.8, and 3.9 pmol/microg protein for 5 minutes, respectively), whereas 6-keto-prostaglandin F1alpha production was not significantly different in the 3 groups.. The data suggest that the fetoplacental vascular response to preeclampsia is to increase production of cyclic guanosine monophosphate, perhaps to maintain vessel dilatation and maximum flow through placental villi. In fetal growth restriction the umbilical vein endothelial cells do not or cannot respond to chronic hypoxia by increasing cyclic guanosine monophosphate, which may lead to fetoplacental vasoconstriction.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Arginine; Case-Control Studies; Cells, Cultured; Cyclic GMP; Endothelium, Vascular; Female; Fetal Growth Retardation; Humans; Kinetics; NG-Nitroarginine Methyl Ester; Nitric Oxide; Pre-Eclampsia; Pregnancy; Scintillation Counting; Statistics, Nonparametric; Tritium; Umbilical Veins

1. In pre-eclampsia, a functional change occurs in the role played by endothelium-derived nitric oxide (NO) in the regulation of smooth muscle contraction in resistance arteries. We investigated the underlying mechanism in human omental resistance arteries from normotensive pregnant and pre-eclamptic women in the presence of diclofenac (an inhibitor of cyclo-oxygenase). 2. In endothelium-intact strips, the sensitivity to 9,11-epithio-11,12-methano-thromboxane A2 (STA2) was significantly higher in pre-eclampsia, and this was not modified by either NG-nitro-L-arginine (L-NNA, an inhibitor of NO synthase) or removal of the endothelium. 3. Bradykinin and substance P each produced an endothelium-dependent relaxation of the STA2-induced contraction in both groups, although the relaxation was significantly smaller for pre-eclampsia. L-NNA markedly attenuated the endothelium-dependent relaxation in the normotensive pregnant group but not in the pre-eclamptic group. 4. In the presence of L-NNA, the relaxation induced by sodium nitroprusside (SNP) on the STA2 contraction was significantly smaller for pre-eclamptic than for normotensive pregnant women. 5. In endothelium-denuded strips, the relaxation induced by 8-para-chlorophenyl thio-guanosine-3', 5'-cyclic monophosphate (8-pCPT-cGMP) on the STA2 contraction was significantly less for pre-eclampsia. 6. In beta-escin-skinned strips from both groups of women, 8-pCPT-cGMP (1-10 microM) concentration-dependently attenuated the contraction induced by 0.5 microM Ca2+. However, its relaxing action was significantly weaker in pre-eclampsia. 7. It is suggested that the weaker responsivene to NO seen in strips from pre-eclamptic women may be partly due to a reduced smooth muscle responsiveness to cyclic GMP.

Topics: Adult; Benzimidazoles; Bradykinin; Calcium; Calcium Channel Agonists; Cyclic GMP; Cyclooxygenase Inhibitors; Endothelium, Vascular; Female; Humans; In Vitro Techniques; Mesenteric Arteries; Muscle Contraction; Muscle, Smooth; Nitric Oxide; Nitric Oxide Synthase; Nitroprusside; Omentum; Potassium; Pre-Eclampsia; Pregnancy; Substance P; Thromboxane A2; Vasodilation

In chronically hypertensive (CH), preeclamptic (PE), and normotensive pregnant women (N), we investigated ex vivo platelet aggregation in response to L-arginine (L-Arg) and sodium nitroprusside (SN), which are respectively the substrate and donor of nitric oxide (NO).. Platelet aggregation was determined with a dual-channel aggregometer by measuring transmittance of light through the sample in comparison to platelet poor plasma, as a reference. Aggregation induced by adenosine diphosphate was continuously recorded for 3 min and measured before and after preincubation with L-Arg and SN.. Preincubation with L-Arg significantly reduced platelet aggregation in N and CH patients (p < 0.05) but not in PE women. Preincubation with SN affected aggregation in PE women also (p < 0.001). No correlation was found between platelet response to L-Arg or SN stimuli and the severity of hypertensive disorders expressed as week of gestation at delivery or birth weight.. The present study demonstrates that a decreased platelet sensitivity to L-Arg characterizes PE women, whereas SN maintains its antithrombotic power. This impairment seems to be specific for PE, because platelets of CH patients utilize L-Arg normally. This finding supports the involvement of the L-Arg-NO pathway in the pathogenesis of the procoagulative features of PE and probably in the onset of the disease. The maintained response to SN in PE patients suggests a possible therapeutical use of NO donors in the disease.

Topics: Adult; Analysis of Variance; Antihypertensive Agents; Arginine; Birth Weight; Blood Pressure; Case-Control Studies; Cesarean Section; Chronic Disease; Cross-Sectional Studies; Cyclic GMP; Female; Gestational Age; Humans; Hypertension; Nitric Oxide Donors; Nitroprusside; Platelet Aggregation; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Statistics, Nonparametric

We investigated the characteristic changes in histamine-induced, endothelium-derived nitric oxide (NO)-mediated relaxation in human omental resistance arteries seen in pre-eclampsia. Isometric contraction was provoked by a stable analogue of thromboxane A(2) in endothelium-intact strips from both pre-eclamptic and normotensive pregnant women. Histamine (0.3 nM-10 microM) produced a concentration-dependent relaxation of this contraction in both groups. The magnitude of the relaxation induced by histamine (1 microM) was significantly smaller in pre-eclampsia both in the presence and absence of famotidine (H(2)-receptor blocker). In the presence of famotidine, L-N(G)-nitroarginine significantly attenuated the histamine-induced relaxation in strips from normotensive pregnant women but not in those from pre-eclamptic women. The relaxation induced by human atrial natriuretic peptide (0. 1 nM-1 microM) was also significantly smaller in the pre-eclamptic group. It is concluded that the histamine-induced, endothelium-derived NO-mediated relaxation (mediated via H(1)-receptors) is down-regulated in resistance arteries in pre-eclampsia and we suggest that this is due, at least in part, to an attenuation of the action of cyclic GMP in smooth muscle cells.

Topics: Adult; Arteries; Atrial Natriuretic Factor; Cyclic GMP; Down-Regulation; Endothelium, Vascular; Famotidine; Female; Histamine; Humans; Isometric Contraction; Muscle, Smooth, Vascular; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Nitroarginine; Pre-Eclampsia; Pregnancy; Pyrilamine; Receptors, Histamine H1; Receptors, Histamine H2; Vascular Resistance; Vasodilation

We tested the hypothesis that nitric oxide (NO) biosynthesis increases during normal human pregnancy and decreases in preeclampsia. The major metabolites of NO, nitrate and nitrite (NO(x)), were measured in both the plasma and 24-h urine of women subjected to a reduced NO(x) diet. In this way, the plasma and urinary levels mainly reflected endogenous production rather than dietary intake. Moreover, we assessed cGMP, a second messenger of NO, in the same samples. Both NO(x) and cGMP assays were validated in our laboratory. We first conducted a cross-sectional study of nonpregnant women (n = 15), normal pregnant women in the first (n = 9), second (n = 17) and third (n = 22) trimesters, as well as women with preeclampsia (n = 15) and transient hypertension of pregnancy (n = 7). We also performed a serial study in the same women (n = 9) before, during, and after pregnancy. Taken together, the results of the two investigations suggested marked increases in cGMP production especially during the first trimester when the maternal circulation is rapidly vasodilating. In contrast, whole body NO production as estimated by the plasma level and urinary excretion of NO(x) was not elevated during the first trimester. Finally, unequivocal demonstration of reduced NO biosynthesis in preeclampsia was not forthcoming.

Topics: Adult; Cross-Sectional Studies; Cyclic GMP; Diet; Female; Humans; Longitudinal Studies; Nitric Oxide; Pre-Eclampsia; Pregnancy; Time Factors

Our purpose was to evaluate plasma levels of brain natriuretic peptide (pBNP) and cyclic guanosine monophosphate (pcGMP) in preeclamptic patients and controls.. Blood samples were obtained from 35 patients with preeclampsia and from the same women during the subsequent puerperal period. The control group consisted of normotensive pregnant women, matched with the patients for age, gestational age, and parity. The concentrations of pBNP and pcGMP were determined by the RIA method. Statistical analysis was performed using the Mann-Whitney's U test.. The pBNP level in the preeclampsia group was significantly increased, to 7-fold that of the control group. The pcGMP level was 50% higher in the preeclampsia group than in the control group, but this was not significant. Both the pBNP level and the pcGMP level in the puerperal period did not significantly differ between the patients and the controls.. The pBNP concentrations increased in the preeclamptic women, and then these compensations were normalized in the puerperal period.

Topics: Adult; Case-Control Studies; Cyclic GMP; Female; Humans; Natriuretic Peptide, Brain; Pre-Eclampsia; Pregnancy; Reference Values

Several observations suggest that endothelial cell dysfunction is a central pathophysiologic event of preeclampsia. Endothelin-1 (ET-1) is a vasoconstrictor peptide of the endotheliocyte and is increased in the sera of preeclamptic patients. The aim of this study was to investigate the possible regulatory mechanisms between ET-1 and nitric oxide (NO) production in cultured placental endotheliocytes. We report that endothelial cells of arterial placental blood vessels show a dysfunctional mechanism of negative feedback regulation of ET-1 production by cGMP or insufficient NO release in response to a stimulus in the form of an increasing ET-1 concentration.

Topics: Cells, Cultured; Culture Media; Cyclic GMP; Endothelin-1; Endothelium, Vascular; Feedback; Female; Humans; Nitric Oxide; Placenta; Pre-Eclampsia; Pregnancy

To determine the effects of the nitric oxide (NO) precursor L-arginine on the airway NO concentration in patients with preeclampsia.. NO was measured by a noninvasive chemiluminescence technique in air sampled directly from nasal and oral cavities during expiration before and during L-arginine infusion in 9 preeclamptic and 10 control pregnancies. Maternal blood pressure and heart rate were simultaneously recorded, and blood was sampled for analyses of cyclic guanosine monophosphate (cGMP) and nitrate.. Basal nasal and orally exhaled NO and the increment in nasal NO concentration during L-arginine infusion were similar in both groups. Basal plasma and platelet cGMP concentrations were similar in both groups. Following L-arginine infusion, plasma cGMP levels were significantly higher in preeclamptics (p < 0.01), while platelet cGMP was unaffected in both groups. Basal plasma nitrate was significantly higher in preeclamptics (p < 0.01), and this difference was not altered following infusion. Blood pressure and heart rate remained unaffected by the procedure in both groups.. Blood pressure did not decrease in the preeclamptics following L-arginine infusion, despite a significant increase in nasal NO sampled during breathhold and a concomitant increase in plasma cGMP, possibly reflecting an endogenous NO production. These results do not support the idea of a generalized decrease in NO production being a major cause of hypertension in preeclampsia.

Topics: Adult; Arginine; Blood Pressure; Breath Tests; Cyclic GMP; Female; Heart Rate; Humans; Luminescent Measurements; Mouth; Nitrates; Nitric Oxide; Nose; Pre-Eclampsia; Pregnancy

Platelet activation occurs in early pregnancy in women at risk of developing pre-eclampsia. Cytokines have been implicated in the pathogenesis of pre-eclampsia, so we determined the effects of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) on the in vitro aggregation of human platelets. IL-1beta increased aggregation of platelets from non-pregnant and pre-eclamptic women, and inhibited the aggregation of platelets from normal pregnant women. This latter effect was linked to a diminished P-selectin expression on ADP-stimulated whole blood platelets in normal pregnant women (p = 0.011). Platelet aggregation in response to ADP was found to be inhibited after preincubation with TNF-alpha in non-pregnant (38%, p = 0.01) and in normal pregnant women (54%, p = 0.001) and not affected in pre-eclamptic women. The inhibitory effects of TNF-alpha were mediated through the P75 receptor for TNF-alpha.

Topics: Adenosine Diphosphate; Adult; Blood Platelets; Cyclic AMP; Cyclic GMP; Female; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Middle Aged; Nitric Oxide; P-Selectin; Platelet Aggregation; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Recombinant Proteins; Second Messenger Systems; Sialoglycoproteins; Thromboxane B2; Tumor Necrosis Factor-alpha

Cyclic GMP, endothelin and prostaglandin E2 (PGE2) all have systemic vasoactive properties (with cyclic GMP acting as a second messenger of nitric oxide). Intrarenally they act as natriuretics and urinary levels reflect intrarenal production. Cyclic GMP and PGE2 also act as important inhibitors of platelet activation and thrombosis. The purpose of this study was to determine if urinary levels of cyclic GMP, endothelin, and PGE2 differ in preeclamptic as compared to normal pregnancies. Parameters were compared in 13 normotensive, nonpreeclamptic pregnancies, and 32 preeclamptic pregnancies. Preeclamptic women had significantly lower levels of urinary cyclic GMP (0.67 +/- 0.12 vs. 2.1 +/- 0.5 nmol/g creatinine), endothelin (0.88 +/- 0.09 vs. 3.75 +/- 1.4 ng/g creatinine), and PGE2 (26 +/- 4 vs. 9 ng/g creatinine) as compared to normals (p < 0.05). Intrarenal production of cyclic GMP, endothelin, and PGE2 are all disturbed in preeclampsia and may have implications in the sodium retention, hypertension, and intrarenal thrombosis and vasospasm of preeclamptic pregnancy.

Topics: Adult; Blood Pressure; Cyclic GMP; Dinoprostone; Endothelins; Female; Humans; Pre-Eclampsia; Pregnancy; Pregnancy Outcome

One of the possible mechanisms responsible for pre-eclampsia is a loss of efficiency of the L-arginine-nitric oxide pathway with subsequent inactivation of the guanylyl cyclases of the vascular smooth muscle cells. As a result there should be a decrease in plasma cyclic 3'-5' guanosine monophosphate (cGMP) concentrations in pre-eclampsia. We assessed the behavior of this nucleotid in the plasma of pre-eclamptic women.. Sixteen pre-eclamptic women, 16 normotensive pregnant women matched for gestational age and six nonpregnant controls were investigated. Arterial blood pressure was recorded at inclusion time and then once-a-day until the fourth day after delivery concomitantly with the collection of blood samples for determining plasma cGMP, atrial natriuretic peptides (ANP), creatinine, uric acid and platelet counts. Also 24 h urines were simultaneously collected to calculate renal clearance of cGMP.. Before the initiation of antihypertensive treatment, plasma cGMP levels were significantly higher (p < 0.01) in pre-eclampsia women as compared both to pregnant normotensive controls and nonpregnant women (7.02 +/- 0.9 versus 4.8 +/- 0.76 versus 1.93 +/- 0.15 pmol.ml-1, p < 0.01). Under antihypertensive treatment, cGMP levels decreased significantly (p < 0.05) to 5.48 +/- 0.9 pmol.ml-1. The increase of plasma cGMP was associated with high ANP levels; the likelihood that a renal impairment could account for an increase in plasma cGMP was ruled out because the clearance of creatinine was not impaired. Similarly the possibility of a significant linear correlation between cGMP levels and blood pressure values or biological data was excluded in these women.. Plasma cGMP concentrations are increased in pre-eclampsia. They decrease to control values when blood pressure returns to normal values; they indicate enhanced guanylyl cyclase activation by ANP and additional factors, but cannot be considered as a direct index of the severity of pre-eclampsia.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Female; Guanylate Cyclase; Humans; Hypertension; Nitric Oxide; Parity; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular

To elucidate the role of the L-arginine:nitric oxide pathway in pregnancy and pre-eclampsia.. Pregnant women (nulliparous, age <25 years). Normotensive pregnancy (n=22) was defined when blood pressure remained at levels of <120/80 mmHg and there was no proteinuria. Women with pre-eclampsia (n=22) had blood pressure measurements of >140/90 mmHg and proteinuria of >300 mg/l. Nonpregnant normotensive women (n=22) were studied as controls.. Blood samples were taken for measurements of ionised calcium, atrial natriuretic factor, cyclic guanosine 3'5' monophosphate (GMP),arginine and asymmetric dimethylarginine. Urine samples were collected for determination of cyclic GMP excretion. Cyclic GMP concentrations were also determined in 12 women with severe pre-eclampsia before and after treatment with hydralazine.. L-arginine, asymmetric dimethylarginine and atrial natriuretic factor were not different in any group. Cyclic GMP concentrations in plasma [0.94 (SD 0.23) nM] as well as in urine [50.1 (SD 15.7) microM] were increased significantly (P<0.05) in normal pregnancy compared to nonpregnant controls [plasma mean 0.46 (SD 0.12) nM and urine mean 18.4 (SD 10.3) microM], but not in the pre-eclampsia group [plasma mean 0.48 (SD 0.10) nM and urine mean 24.1 (SD 14.5) microM]. Concentrations of cyclic GMP in plasma and urine increased significantly (P<0.05) in women treated with hydralazine.. The differences in cyclic GMP concentrations may reflect differences in nitric oxide production. Hydralazine increases cyclic GMP concentrations in severely pre-eclamptic women. This action could explain the antihypertensive effect of hydralazine.

Topics: Adult; Arginine; Birth Weight; Blood Pressure; Cyclic GMP; Female; Humans; Hydralazine; Nitric Oxide; Pre-Eclampsia; Pregnancy; Vasodilator Agents

To investigate systemic and fetal-placental nitric oxide synthesis by biochemical and molecular biology means in normal human pregnancy and pre-eclampsia.. Three groups of women were studied: healthy pregnant women (n = 8), pregnant women with pre-eclampsia (n = 8), and age-matched nonpregnant controls (n = 8). Pre-eclamptic patients were treated with nifedipine (30-60 mg/day) for severe hypertension. Systemic nitric oxide synthesis was assessed in normal pregnant women at weeks 18-21, 29-32 and 38-39 and in pre-eclamptic women on admission to the hospital (29-32 weeks, 30 on average), before the morning nifedipine administration. Nonpregnant women were studied twice at four-week intervals as controls. The pattern of nitric oxide biosynthesis in fetal-placental circulation was studied in normal and pre-eclamptic women at the delivery.. Mario Negri Institute for Pharmacological Research, Bergamo, and the Division of Obstetrics and Gynaecology of the University of Brescia.. Plasma cGMP levels and platelet nitric oxide synthesis, assessed by measuring the conversion of [3H]L-arginine to [3H]L-citrulline as well as intracellular cGMP, were evaluated. Constitutive nitric oxide synthase (EC-NOS) gene expression by Northern blot analysis and nitric oxide release by the conversion of [3H]L-arginine to [3H]L-citrulline were assessed in umbilical vein endothelial cells (HUVEC) and in placenta. Inducible nitric oxide synthase activity was also evaluated in HUVEC exposed to tumour necrosis factor alpha (TNF alpha) and in placenta homogenates incubated in calcium free medium.. Plasma cGMP was higher in both normal pregnant and pre-eclamptic women than in nonpregnant controls. In normal pregnancy cGMP rose as early as 18-21 weeks and remained elevated throughout pregnancy. [3H]L-citrulline production and intracellular cGMP were comparable in platelets from all women. EC-NOS gene expression and nitric oxide synthesis were identical in HUVEC and placenta from normal pregnant and pre-eclamptic women.. Systemic levels of CGMP, the nitric oxide second messenger, are increased in normal pregnancy. Excessive nitric oxide production does not derive from platelets. Pre-eclampsia is not associated with changes in fetal-placental nitric oxide synthesis.

Topics: Adult; Arginine; Blood Platelets; Blotting, Northern; Citrulline; Cyclic GMP; Female; Humans; Nitric Oxide; Nitric Oxide Synthase; Pre-Eclampsia; Pregnancy

This study was undertaken to observe the effects of organic or inorganic calcium antagonists and to investigate the involvement of cyclic nucleotides in regulating the vascular tone in the chorionic artery from normal or preeclamptic placenta. KCI and prostaglandin (PG) F2 alpha produced marked and constant contractions in chorionic arterial preparations of both normal and preeclamptic placentas. Nifedipine (NIF), verapamil (VER) and diltiazem (DIL) reduced the tension that had been produced by KCI and PGF2 alpha in a concentration-dependent fashion in both preparations, and the potency order of the three agents was NIF > VER > DIL. In preeclamptic arteries, however, the magnitudes of vasodilatation induced by NIF and DIL were much smaller than those in normal chorionic arteries. Mg2+ and Cd2+ also relaxed the tension induced by KCI and PGF2 alpha. In preeclamptic chorionic artery, the vasodilatation induced by Mg2+ was significantly potentiated, while that by Cd2+ was not. Removing endothelium did not alter cyclic GMP content in both preparations. In both preparations contracted by PGF2 alpha, nitroprusside markedly increased cyclic GMP content, but neither cyclic GMP nor cyclic AMP content was affected by acetylcholine, NIF, isopro-terenol, or Mg2+. The above results suggest that neither cyclic AMP nor cyclic GMP is involved in regulating the vascular tone of chorionic artery and that sensitivity of the artery in preeclampsia to the inhibitory action of calcium antagonist might be different from that in normal placenta.

Topics: Arteries; Calcium Channel Blockers; Cyclic AMP; Cyclic GMP; Dinoprost; Female; Humans; Placenta; Potassium Chloride; Pre-Eclampsia; Pregnancy; Vasoconstriction

To determine whether the antepartum and postpartum plasma nitric oxide (NO) levels were changed in pregnancy induced hypertension (PIH).. 30 patients with PIH and 30 healthy women in their late pregnancy were studied. The antepartum and postpartum plasma NO2-/NO2- levels, the stable metabolic end products of NO, and cyclic guanosine monophosphate (cGMP) were measured with greiss reagent.. (1) The plasma concentration of NO2-/NO2- and cGMP in patients with PIH decreased significantly when compared with that of healthy pregnant women (P < 0.01). (2) The concentration of antepartum plasma NO2-/NO2- was markedly lower than that of postpartum one in PIH patients (P < 0.01). (3) There was a negative correlation between the plasma NO2-/NO3- level and systolic blood pressure in PIH (P < 0.01). (4) A positive correlation was seen between plasma NO2-/NO3- levels and cGMP levels in PIH patients (P < 0.01).. The decrease of NO synthesis may be one of the important factors responsible for PIH.

Topics: Adult; Cyclic GMP; Female; Humans; Nitric Oxide; Nitric Oxide Synthase; Pre-Eclampsia; Pregnancy

Recently, we showed that levels of circulating free fatty acids are increased in women who later develop pre-eclampsia long before the clinical onset of the disease. Among the serum free fatty acids, oleic-, linoleic-, and palmitic acid were found to be increased by 37, 25 and 25%, respectively. In the present study we asked if these free fatty acids can interfere with endothelial cell functions. Cultured endothelial cells were exposed to linoleic-, oleic- and palmitic acid in concentrations ranging from 0.016 to 0.133 mumol ml-1, resulting in molar ratios of free fatty acids to albumin of 0.2-1.6. We found that among these fatty acids, linoleic acid reduced the thrombin-stimulated prostacyclin release by 30-60%, oleic acid by 10-30%, whereas palmitic acid had no effect. Endothelial cells incubated in presence of linoleic acid showed a concentration-dependent reduction in prostacyclin release in response to thrombin, and cells incubated with linoleic acid for up to 28 h, showed a reduced thrombin-induced prostacyclin release at every time point. Endothelial level of cGMP mainly reflected the synthesis of endothelium-derived relaxing factor/nitrogen monoxide (EDRF/NO), since blocking of the endogenous production of EDRF/NO with N-omega-nitro-L-arginine, resulted in about 90% reduction in cGMP-content of the endothelial cells. Incubation with linoleic acid reduced the endothelial cGMP level by 70%. Linoleic acid reduced the endothelial cells ability to inhibit platelet aggregation by 10-45%, (p = 0.0019). It was concluded that linoleic acid impedes the ability of the endothelial cells to produce prostacyclin and cGMP, and to inhibit platelet aggregation.

Topics: Cells, Cultured; Cyclic GMP; Endothelium, Vascular; Epoprostenol; Fatty Acids, Nonesterified; Female; Humans; Linoleic Acid; Linoleic Acids; Nitric Oxide; Oleic Acid; Oleic Acids; Palmitic Acid; Palmitic Acids; Platelet Aggregation; Pre-Eclampsia; Pregnancy

1. Platelet activation in vivo occurs in healthy pregnancy and is more pronounced in pre-eclampsia. 2. This study has investigated: (i) the inhibitory potency of the nitric oxide donors 3-morpholinosydnonimine and sodium nitroprusside, on the platelet release reaction in vitro in non-pregnant, healthy pregnant and pre-eclamptic women; (ii) the concentration of cyclic GMP during incubation of washed platelets with sodium nitroprusside in a separate group of non-pregnant, healthy pregnant and pre-eclamptic women. 3. The half-maximal inhibitory concentration of sodium nitroprusside, in the presence of a phosphodiesterase inhibitor, for inhibition of the platelet release reaction was lower in the pre-eclamptic subjects than in the non-pregnant subjects (P < 0.05). 4. Several of the pre-eclamptic women were studied again postnatally. The half-maximal inhibitory concentrations of sodium nitroprusside and 3-morpholinosydnonimine were higher in the postnatal than in the antenatal sample (P < 0.02). 5. Peak platelet cyclic GMP responses to sodium nitroprusside were significantly higher in the pre-eclamptic women than in the healthy pregnant and non-pregnant women. 6. These results suggest that platelets are more sensitive to the inhibitory effects of nitric oxide donors in pre-eclampsia.

Topics: Adolescent; Adult; Blood Platelets; Cells, Cultured; Cyclic GMP; Dose-Response Relationship, Drug; Female; Humans; Molsidomine; Nitric Oxide; Nitroprusside; Platelet Activation; Pre-Eclampsia; Pregnancy

To compare normal pregnancy with pregnancy-induced hypertension (PIH)/preeclampsia with respect to the effects of acute volume expansion on plasma atrial natriuretic peptide (ANP), cyclic guanosine monophosphate (cGMP) and fetal-maternal circulation.. Observational study.. University hospital.. Fifteen women with PIH/preeclampsia and 15 healthy pregnant controls.. Before and after 30 minutes' infusion of a crystalloid solution (15 ml/kg), maternal venous blood was sampled for ANP and cGMP analysis and echocardiographic and Doppler investigations were performed.. Basal median (range) ANP and cGMP levels were significantly higher in the PIH/preeclampsia group compared to the controls: 6.5 (3.8-30.4) compared to 3.9 (2.0-6.7) pmol/l, p < 0.01 and 5.8 (2.4-11.6) compared to 4.0 (2.3-10.8) nmol/l, p < 0.05. The response to volume load was enhanced: 4.6 (-4.5-21.8) compared to 0.7 (-4.1-8.8), p < 0.05 and 2.9 (0.1-10.9) compared to 1.2 (-5.0-6.0), p < 0.05, respectively. Systemic vascular resistance was initially higher in the patient group, 22.3 (14.1-36.7) compared to 15.6 (10.0-25.5) peripheral resistance units, p < 0.01 but the response to volume load was similar in both groups (12-13% decrease). The pulsatility index of the uterine artery, 0.85 (0.46-1.38) compared to 0.72 (0.49-1.26) and umbilical artery 0.89 (0.66-1.57) compared to 0.97 (0.74-1.31) did not differ between the groups. Volume expansion did not affect any of these variables.. The pulsatility index of the uterine artery remained unaffected in both preeclamptic patients and healthy controls despite an increase of ANP and cGMP concentration and a systemic vasodilatation during acute volume expansion. This finding may indicate the absence of a vasodilation of the uteroplacental vascular bed.

Topics: Atrial Natriuretic Factor; Blood Circulation; Blood Volume; Cyclic GMP; Female; Fetal Blood; Humans; Hypertension, Renal; Maternal-Fetal Exchange; Pre-Eclampsia; Pregnancy; Pregnancy Trimester, Third; Pulsatile Flow; Vascular Resistance

Our objective was to determine if maternal urinary cyclic guanosine monophosphate levels are altered in preeclampsia.. Aliquots from 24-hour urine samples collected from 57 women with preeclampsia and 14 normotensive pregnant women in the third trimester of pregnancy were assayed for urinary cyclic guanosine monophosphate. Urinary cyclic guanosine monophosphate values were expressed per milligram of urinary creatinine to standardize for renal function.. There was no difference in gestational age at time of urine collection between the two groups. Urinary cyclic guanosine monophosphate levels (mean +/- SD) were similar between normotensive and preeclamptic pregnant women (751 +/- 498 vs 632 +/- 363 pmol/mg urinary creatinine, respectively, p = 0.12). Preeclamptic women receiving magnesium sulfate had significantly higher levels of urinary cyclic guanosine monophosphate than those not receiving magnesium sulfate (786 +/- 360 vs 555 +/- 344 pmol/mg urinary creatinine, respectively, p = 0.02).. These preliminary results indicated that cyclic guanosine monophosphate excretion increases in patients with preeclampsia during magnesium sulfate infusion. The vascular smooth muscle relaxation effects of magnesium sulfate may be mediated by directly increasing cyclic guanosine monophosphate production or indirectly through endothelium-derived relaxing factor.

Topics: Cyclic GMP; Female; Gestational Age; Humans; Magnesium Sulfate; Pre-Eclampsia; Pregnancy; Radioimmunoassay

To assess the effect of endogenous human atrial natriuretic peptide on the vascular system in preeclampsia, the circadian variations of plasma human atrial natriuretic peptide, cyclic guanosine 3'5'-monophosphate, cyclic adenosine 3'5'-monophosphate, and blood pressure were measured. In severe preeclamptic women, the mean 24-hour values of human atrial natriuretic peptide and cyclic guanosine 3'5'-monophosphate rose significantly compared with those in normal nonpregnant and pregnant women. Also, in severe preeclamptic women, circadian variations of plasma atrial natriuretic peptide, cyclic guanosine 3'5'-monophosphate, and blood pressure confirmed the same circadian rhythm with acrophase during the middle of the night. Plasma cyclic adenosine 3'5'-monophosphate values did not differ significantly among the three groups and did not confirm a circadian rhythm. These results suggest that plasma human atrial natriuretic peptide may not strongly influence blood pressure, although it may induce the relaxation of vascular smooth muscles via the cyclic guanosine 3'5'-monophosphate system in preeclampsia.

Topics: Adult; Atrial Natriuretic Factor; Blood Pressure; Circadian Rhythm; Cyclic AMP; Cyclic GMP; Female; Humans; Pre-Eclampsia; Pregnancy

Topics: Cyclic AMP; Cyclic GMP; Female; Humans; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy, Prolonged; Uterine Inertia