cyclic-gmp and Fetal-Growth-Retardation

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

Fetal growth restriction (FGR) is the impairment of the biological growth potential of the fetus and often leads to adverse pregnancy outcomes. The molecular mechanisms for the development of FGR, however, are still unclear. The purpose of this study is to identify critical genes associated with FGR through an integrated bioinformatics approach and explore the potential pathogenesis of FGR.. We downloaded FGR-related gene microarray data, used weighted gene co-expression network analysis (WGCNA), differentially expressed genes (DEGs), and protein-protein interaction (PPI) networks to screen hub genes. The GSE24129 gene set was used for validation of critical gene expression levels and diagnostic capabilities.. A weighted gene co-expression network was constructed, and 5000 genes were divided into 12 modules. Of these modules, the blue module showed the closest relationship with FGR. Taking the intersection of the DEGs and genes in the blue module as pivotal genes, 277 genes were identified, and 20 crucial genes were screened from the PPI network. The GSE24129 gene set verified the expression of 20 genes, and CXCL9, CXCR3, and ITGAX genes were identified as actual pivotal genes. The expression levels of CXCL9, CXCR3, and ITGAX were increased in both the training and validation sets, and ROC curve validation revealed that these three pivotal genes had a significant diagnostic ability for FGR. Single-gene GSEA results showed that all three core genes activated "hematopoietic cell lineage" and "cell adhesion molecules" and inhibited the "cGMP-PKG signaling pathway" in the development of FGR. CXCL9, CXCR3, and ITGAX may therefore be closely associated with the development of FGR and may serve as potential biomarkers for the diagnosis and treatment of FGR.

Topics: CD11c Antigen; Cell Lineage; Computational Biology; Cyclic GMP; Female; Fetal Growth Retardation; Gene Expression Profiling; Gene Regulatory Networks; Humans; Pregnancy

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

Intrauterine growth restriction (IUGR) is a leading cause of perinatal mortality and morbidity, and is linked to an increased risk to develop chronic diseases in adulthood. We previously demonstrated that IUGR is associated, in female neonates, with a decreased nitric oxide (NO)-induced relaxation of the umbilical vein (UV). The present study aimed to investigate the contribution of the smooth muscle components of the NO/cyclic GMP (cGMP) pathway to this alteration.. UVs were collected in growth-restricted or appropriate for gestational age (AGA) human term newborns. Soluble guanylyl cyclase (sGC) and cGMP-dependent protein kinase (PKG) were studied by Western blot, cGMP production by ELISA and cyclic nucleotide phosphodiesterases (PDEs) activity using a colorimetric assay. Contribution of PDEs was evaluated using the non-specific PDEs inhibitor 3-isobutyl-1-methylxanthine (IBMX) in isolated vessel tension studies.. NO-induced relaxation was reduced in IUGR females despite increased sGC protein and activity, and some increase in PKG protein compared to AGA. In males, no significant difference was observed between both groups. In the presence of IBMX, NO-stimulated cGMP production was significantly higher in IUGR than AGA females. Pre-incubation with IBMX significantly improved NO-induced relaxation in all groups and abolished the difference between IUGR and AGA females.. IUGR is associated with sex-specific alterations in the UV's smooth muscle. The impaired NO-induced relaxation observed in growth-restricted females is linked to an imbalance in the NO/cGMP pathway. The beneficial effects of IBMX suggest that PDEs are implicated in such alteration and they could represent promising targets for therapeutic intervention.

Topics: Adult; Case-Control Studies; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Female; Fetal Growth Retardation; Fetus; Humans; Infant, Newborn; Male; Nitric Oxide; Pregnancy; Sex Characteristics; Signal Transduction; Soluble Guanylyl Cyclase; Umbilical Veins; Vasodilation

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

Diminished vasodilator activity during pregnancy, which augments vascular responses to vasoconstrictors, is one reason for the onset of pre-eclampsia and superimposed pre-eclampsia. It is known that Dahl salt-sensitive (Dahl-S) rats develop salt-sensitive hypertension like African-Americans. The present study attempted to assess the changes and the interactions of the NOS-NO-sGC-cGMP and NP-NPR-cGMP systems in the hypertensive placenta using Dahl-S rats as an animal model of superimposed pre-eclampsia.. Pregnant Dahl-S rats were fed a high-salt diet to induce the development of hypertension and fetal growth restriction. Using these rats, we investigated the regulation of these two vasodilatation systems, including the kinetics of cyclic guanosine monophosphate (cGMP), soluble guanylate cyclase (sGC), endothelial nitric oxide synthase (NOS), cytokine-inducible NOS, natriuretic peptides (NP) (atrial NP, brain NP and C-type NP), and NP receptors (NPR) (NPR-A, NPR-B, NPR-C).. Dahl-S rats fed a high-salt diet exhibited hypertension, fetal growth restriction and thickening of the walls in decidual vessels. The placental cGMP level in the rats fed the high-salt diet was significantly decreased compared with that in controls. The expression levels of endothelial NOS and cytokine-inducible NOS mRNA increased significantly, while that of sGCα2-sunbnit declined significantly. Messenger RNA levels of NPR-C, a clearance-type receptor of NP, declined significantly, whereas those of NP and their functional receptors NPR-A and NPR-B were unchanged.. As Dahl-S rats with excess salt-loading during pregnancy exhibited pathological changes similar to those observed in female humans with pre-eclampsia/superimposed pre-eclampsia, this rat could be useful as an animal model of superimposed pre-eclampsia. In the placentas of hypertensive Dahl-S rats, vasodilatation seemed to be disturbed by the deregulation of both the NO-sGC-cGMP and NP-NPR-cGMP systems.

Topics: Animals; Cyclic GMP; Female; Fetal Growth Retardation; Hypertension; Nitric Oxide; Placenta; Pregnancy; Rats; Rats, Inbred Dahl; Soluble Guanylyl Cyclase

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

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

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

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

In a study of endogenous nitric oxide production in growth-retarded, very preterm newborns (<32 wk GA), urinary NOx/creatinine ratio and plasma guanosine 3',5'-cyclic monophosphate levels were determined during the early neonatal period. Newborns were divided into three groups: appropriate-for-gestational-age (AGA, n = 19), moderately small-for-gestational-age (SGA, n = 13) and severely SGA (n = 6) infants. Severely SGA infants showed significant higher values of nitric oxide derivatives during the first 24 h of life compared with the other groups.. An increased NO production is found in SGA infants during the first 24 h after birth. This may reflect an increased intrauterine nitric oxide production in the feto-placental circulation found in cases with intrauterine growth retardation,

Topics: Analysis of Variance; Chi-Square Distribution; Creatinine; Cyclic GMP; Fetal Growth Retardation; Humans; Infant, Newborn; Infant, Small for Gestational Age; Nitric Oxide; Statistics, Nonparametric

The purpose of this study was to evaluate whether cordocentesis is associated with the release of vasoactive substances and whether there are differences between normally grown and growth-restricted fetuses.. 6-Keto-prostaglandin F1 alpha (the stable metabolite of prostacyclin), endothelin-1, and cyclic guanosine monophosphate were measured in fetal blood at the beginning and closing of cordocentesis in 30 normally grown fetuses and 25 growth-restricted fetuses. This latter group was characterized by abnormal Doppler index values in umbilical artery and middle cerebral artery, suggestive of chronic hypoxemia as the causative factor of the impaired growth. In six growth-restricted fetuses bradycardia occurred at the end of the procedure. Umbilical artery pulsatility index was measured by Doppler ultrasonography immediately before and after the procedure.. The median interval between the two blood samples obtained by cordocentesis was 90 seconds (range 60 to 320 seconds). During this interval a significant rise of 6-keto-prostaglandin F1 alpha (p < or = 0.0001) and endothelin-1 (p = 0.03) was evidenced in normally grown fetuses. The increase in 6-keto-prostaglandin F1 alpha was significantly related (r = 0.52, p = 0.002) to the fall of umbilical artery pulsatility index occurring after the procedure. In growth-restricted fetuses cordocentesis induced a marked increase of endothelin-1 (p = 0.0002), which was significantly related to the severity of acidosis (r = 0.52, p = 0.018), whereas no modifications were evidenced for the other agents tested. The increase of endothelin-1 was higher in those growth-restricted fetuses showing bradycardia at the end of the procedure than in growth-restricted fetuses that did not (p = 0.04). The variations of the vasoactive substances assayed were not significantly related to the type of procedure (transamniotic or transplacental), the amount of blood aspirated during the procedure, the interval elapsing between the first and second samples, the gestational age at which the procedure was performed, and the degree of fetal smallness.. Cordocentesis induces the rapid release of vasoactive substances and the effect differs between normally grown and growth-restricted fetuses. This may explain the different hemodynamic response and the higher rate of complications occurring in the latter group after cordocentesis.

Topics: 6-Ketoprostaglandin F1 alpha; Bradycardia; Cordocentesis; Cyclic GMP; Endothelin-1; Female; Fetal Blood; Fetal Growth Retardation; Gestational Age; Humans; Pregnancy; Pulsatile Flow; Umbilical Arteries

This study has used an in vitro perfusion method to investigate the mechanism by which CRH causes vasodilatation in the human fetal-placental circulation. In normal term placentas, vasodilatory responses to human CRH (24-7000 pmol/L) were examined during submaximal vasoconstriction (100-120 mm Hg) of the fetal-placental vasculature induced by prostaglandin F2 alpha (0.7-2 mumol/L), KCl (50-100 mmol/L), or the thromboxane A2 mimetic, U46619 (0.05-0.5 mumol/L). Infusion of CRH caused a concentration-dependent vasodilatation that was similar in the presence of each constrictor agent (P > 0.05). The CRH antagonist, alpha-helical CRH-(9-41) (200 pmol/L), and a polyclonal CRH antiserum significantly inhibited CRH-induced vasodilatation during constriction with prostaglandin F2 alpha (P < 0.05). Vasodilatory responses to CRH were attenuated by the nitric oxide synthase inhibitor, N omega-nitro-L-arginine (100 mumol/L; P < 0.05), and the guanylate cyclase inhibitor, LY 83583 (1 mumol/L; P < 0.05), but not by the cyclooxygenase inhibitor, indomethacin (3 mumol/L; P > 0.05). In placentas of women with increased fetal vascular resistance, as demonstrated by Doppler ultrasound waveforms in vivo, CRH-induced vasodilatation was significantly reduced (P < 0.05). These results indicate that in the human fetal-placental circulation, CRH causes a vasodilatory response via a nitric oxide-/cGMP-dependent pathway. CRH may play a role in the control of vascular resistance to blood flow in the normal human placenta, and there may be a deficiency in the CRH signaling pathway of placentas with increased fetal vascular resistance.

Topics: Adult; Birth Weight; Corticotropin-Releasing Hormone; Cyclic GMP; Diabetes, Gestational; Dinoprost; Dose-Response Relationship, Drug; Female; Fetal Growth Retardation; Fetus; Humans; In Vitro Techniques; Infant, Newborn; Maternal-Fetal Exchange; Muscle, Smooth, Vascular; Nitric Oxide; Placenta; Potassium Chloride; Pregnancy; Pregnancy Complications; Reference Values; Regression Analysis; Signal Transduction; Vascular Resistance; Vasoconstriction; Vasodilation

Our purpose was to determine the effects of nitric oxide synthase inhibition on maternal and fetal health in the last third of pregnancy.. Pregnant rats were treated from gestational day 13 to day 19 or 20 with the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester, which was administered in the drinking water ad libitum. Control animals received the inactive enantiomer NG-nitro-D-arginine methyl ester or no treatment. Maternal blood pressure, blood chemistry studies, and placenta and pup size were determined. A separate group of rats received nitroprusside sodium in conjunction with NG-nitro-L-arginine methyl ester.. NG-nitro-L-arginine methyl ester caused a dose-dependent reduction in placenta and pup size. Amniotic fluid levels of cyclic guanosine monophosphate were significantly reduced at 0.1 mg/ml but not at higher doses. Hemorrhagic necrosis of fetal hind limbs occurred only with treatment with NG-nitro-L-arginine methyl ester and was prevented by coadministration of nitroprusside sodium. Maternal blood pressure and blood and urine chemistry studies were unaffected by NG-nitro-L-arginine methyl ester.. Chronic reductions of nitric oxide production in the last third of pregnancy result in significant intrauterine growth retardation and hemorrhagic disruptions of hind limbs. Maternal complications were minimal and did not mimic preeclampsia.

Topics: Amniotic Fluid; Animals; Arginine; Cyclic GMP; Dose-Response Relationship, Drug; Female; Fetal Diseases; Fetal Growth Retardation; Fetus; Hemorrhage; Hindlimb; Necrosis; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitroprusside; Placenta; Pregnancy; Pregnancy, Animal; Rats; Rats, Sprague-Dawley