Nitric oxide production with preeclampsia

OBJECTIVE: To clarify production of nitric oxide with pre-eclampsia. METHODS: Production of nitric oxide and elimination of its metabolites, nitrite and nitrate, determines ultimately the level of those metabolites in plasma of subjects whose diets lack them. We measured simultaneously plasma levels and renal clearance of nitrite and nitrate in 20 women with preeclampsia and in 21 healthy pregnant women. Fifteen preeclamptic gravidas were receiving antihypertensive medication and five received betamethasone 1-4 days before the study. Subjects were prescribed low nitrite and nitrate diets for 24 hours and fasted overnight before collection of plasma and urine samples. Nitrite and nitrate were measured spectrophotometrically by Griess reaction. RESULTS: Preeclamptic women had significantly higher plasma levels of nitrite and nitrate (18.1+/-6.2 micromol/L versus 13.0+/-4.3 micromol/L, mean+/-standard deviation [SD], P = .009), which because renal clearance did not differ (0.6+/-0.3 versus 0.7+/-0.3 mL/s), indicated increased production of nitric oxide with preeclampsia that was unaffected by antihypertensives or betamethasone. The mean plasma level of endothelin-1 was increased (5.1+/-1.4 versus 3.6+/-1.0 pg/mL, P < .001), and urinary output of the prostacyclin metabolite 2,3-dinor-6-keto-prostaglandin F1alpha was decreased (39.1+/-18.0 versus 61.3+/-35.6 ng/mmol creatinine, P = .019) with preeclampsia. These two endothelial markers showed no relation to plasma nitrite and nitrate. CONCLUSION: Nitric oxide production was increased with preeclampsia. The biologic significance of increased production is unknown, but it might be compensation for the vasoconstriction of preeclampsia.     

Nitric oxide production is not altered in preeclampsia

Background Preeclampsia remains a disease of theories as the real aetiology has remained elusive. Altered nitric oxide production has been associated with preeclampsia although conflicting results showing elevation, decrease or no change in nitric oxide levels have emerged from previous studies. Objective The aim of the study was to measure the serum levels of nitrate and nitrite in normal pregnancies and pregnancies complicated by pre-eclampsia. Materials and methods Venous blood was extracted from 39 normal pregnant women (control) and 34 women with preeclampsia (study group). Serum concentrations of nitrate and nitrite were determined using the HPLC method. Other special investigations including renal function tests were performed. The patients were managed according to protocol and the outcome of the pregnancies evaluated. Results There was no significant difference in the mean maternal age and gestational age at delivery between the groups. However the mean systolic and diastolic blood pressure of the study group (150.5 mmHg and 98.8 mmHg) were significantly higher than the levels in the control group, (110.86 and 85.5), p<0.0001. There was no significant difference in the mean serum nitrate levels (19.157±13.407 vs. 19.189±16.805) p=0.993. The fetal and maternal outcomes were comparable. Conclusion Our study has demonstrated that there was no alteration in nitric oxide production in preeclampsia, thus contributing to the existing unresolved role of nitric oxide in the pathogenesis of preeclampsia. Further research is called for.     

Initial dosing of inhaled nitric oxide in infants with hypoxic respiratory failure.

BACKGROUND: Inhaled nitric oxide (iNO) is a potent and selective pulmonary vasodilator that decreases pulmonary resistance, and improves ventilation-perfusion matching, thereby improving oxygenation and reducing the need for more invasive therapies. Despite the efficacy of iNO at reducing the use of extracorporeal membrane oxygenation, significant concern remains over the potential toxicity from oxidative derivatives and methemoglobinemia. At present, there is no universal agreement on the lowest effective starting dose. Reported initial doses in the neonatal literature have ranged from 1 to 80 ppm. PURPOSE: To determine if the initial dose of iNO altered the incidence of adverse outcome. METHODS: A cohort of neonates who received iNO for treatment of hypoxic respiratory failure and were entered into the Duke Neonatal Nitric Oxide Registry were evaluated. Neonates with congenital anomalies were excluded. This registry collects data from 36 centers that voluntarily report their experiences with iNO. From this database, the starting dose was recorded and the clinical course was followed. Adverse outcomes were prospectively defined and monitored in the database and included: methemoglobinemia, chronic lung disease, treatment with extracorporeal membrane oxygenation, or death. RESULTS: Data on 476 patients were analyzed. Based on starting doses, records were sorted into three groups: a low-dose group (LDG; <18 ppm, n=57), a mid-dose group (MDG; 18 to 22 ppm, n=320), and a high-dose group (HDG; >22 ppm, n=99). ANOVA showed no statistically significant differences among the groups except for PaO(2)/FiO(2) (p<0.05). Neonates in the high starting dose group were more often classified as treatment failures (21% in the LDG, 27% in the MDG, and 38% in the HDG, p=0.04) and treated with extracorporeal membrane oxygenation (19% in the LDG, 23% in the MDG, and 34% in the HDG, p=0.05) compared to the lower dose groups. In addition, survival without the need for oxygen at 30 days or at discharge was higher in the lower dose groups (93% in the LDG, 84% in the MDG, and 76% in the HDG, p=0.03). Logistic regression, however, showed that the starting dose of iNO did not significantly influence these outcomes when corrected for the degree of hypoxemia (PaO(2)/FiO(2)) at the start of therapy (p>0.1). High initial doses of iNO (>22 ppm) were associated with higher levels of methemoglobin (p< 0.05). There were no differences in mortality or length of hospital stay between the groups. CONCLUSIONS: There is significant variation in the starting dose of iNO between centers. Our retrospective study shows no evidence that higher doses improve outcome. A low concentration of iNO (<18 ppm) should be considered to minimize the potential toxicity of methemoglobin. Furthermore, a well-designed, prospective trial should be undertaken to further define the optimal starting dose.     

Nitric oxide in preterm labor

Synthesis of nitric oxide proceeds in the human myometrium. Decrease of its concentrations can play an essential part in the initiation of uterine contractions in term. Authors suppose, that inhibition of the synthesis of nitric oxide plays a role in premature labour. Concentrations of nitric oxide in women with threatening premature labour were marked. Group I consisted of women with premature departure of amniotic fluid, group II--woman with retained amniotic fluid and with idiopathic contractile activity, group III--woman with departure of amniotic fluid and with idiopathic contractile activity. Concentration of nitric oxide was lower in the group of women with a premature contractile activity in comparison with healthy pregnant women in the same period of pregnancy. Higher concentrations of nitric oxide were observed in the group of patients without contractile activity after departure of amniotic fluid.     

Inhaled nitric oxide in infants >1500 g and <34 weeks gestation with severe respiratory failure.

OBJECTIVE: Inhaled nitric oxide (iNO) use in infants >1500 g, but <34 weeks gestation with severe respiratory failure will reduce the incidence of death and/or bronchopulmonary dysplasia (BPD). STUDY DESIGN: Infants born at <34 weeks gestation with a birth weight >1500 g with respiratory failure were randomly assigned to receive placebo or iNO. RESULTS: Twenty-nine infants were randomized. There were no differences in baseline characteristics, but the status at randomization showed a statistically significant difference in the use of high-frequency ventilation (P=0.03). After adjustment for oxygenation index entry strata, there was no difference in death and/or BPD (adjusted relative risk (RR) 0.80, 95% confidence interval (CI) 0.43 to 1.48; P=0.50), death (adjusted RR 1.26, 95% CI 0.47 to 3.41; P=0.65) or BPD (adjusted RR 0.40, 95% CI 0.47 to 3.41; P=0.21). CONCLUSIONS: Although sample size limits our ability to make definitive conclusions, this small pilot trial of iNO use in premature infants >1500 g and <34 weeks with severe respiratory failure suggests that iNO does not affect the rate of BPD and/or death.     

Nitric oxide for treatment of threatened preterm labor.

OBJECTIVE: The aim of our study was the assessment of effectiveness of nitroglycerin as a donor of nitric oxide, administered in the form of transdermal therapeutic system, applied in the treatment of threatening preterm labor. PATIENTS AND METHODS: The study was carried out on 30 pregnant patients with the symptoms of threatening preterm labor between 27th and 34th week of gestation. The patients were given nitroglycerin in the form of transdermal system releasing 5 mg of nitroglycerin in 24 h. RESULTS: In our study the decrease in contractility and relaxation of uterus was observed in all obstetric patients. No changes in the fetal pulse rate and cardiotocographic tracing in the course of treatment and after completing treatment were observed. CONCLUSION: Nitroglycerin in the form of transdermal therapeutic system releasing nitric oxide may be an effective and safe tocolytic drug, however, further investigation needs to be performed.     

Nitric oxide and peroxynitrite in the perinatal period

Many of the actions of nitric oxide are not due to nitric oxide itself, but rather by the secondary formation of oxidants like peroxynitrite. Peroxynitrite leaves a footprint in the nitration of tyrosine, which helps track the formation of reactive nitric oxide-derived species in diseases and even normal development.     

Nitric oxide metabolites in preterm and induced labor

BACKGROUND: Nitric oxide has potent relaxant effects on the pregnant uterus and has been associated with a quiescent uterus in animal and human studies. Nitric oxide donors have been used to arrest preterm labor and a reduction in nitric oxide production has been reported before the onset of labor. OBJECTIVE: The aim of the study was to estimate the serum levels of nitrate and nitrite in women undergoing spontaneous preterm labor and induced labor. MATERIALS AND METHOD: Venous blood was drawn from 39 patients before the onset of labor (control) and also from 17 patients undergoing induction of labor who were in active labor (study group A), and 24 patients in spontaneous preterm labor (study group B). Serum concentrations of nitrate and nitrite were estimated in the samples using the HPLC method. RESULTS: The maternal age of the patients was similar in all the groups. There was no significant difference in the mean gestational age at delivery between the control and group-A patients (38.86 vs. 38.29 weeks); however, there was a significant difference between the control and group-B patients (38.86 vs. 30.92; p < 0.0001), and between study groups A and B (38.29 vs. 30.92 weeks; p < 0.0001). The mean serum levels of nitrite in groups A and B (0.563 +/- 0.15 and 0.512 +/- 0.13, respectively) were significantly lower than the level in the control group (0.915 +/- 0.13; p < 0.0001). Although the serum nitrate levels in study groups A and B were lower than in the control group, this difference was not significant. The maternal outcome was satisfactory but, as expected, the mean birth weight of the babies in group B (1,665.73 +/- 863.84 g) was significantly lower than the birth weights in the control and group-A patients (p < 0.0001). CONCLUSION: There is a drop in nitric oxide production in active preterm labor and induced labor. These findings need to be confirmed in larger studies to establish the role of nitric oxide in the initiation of labor.     

吸入一氧化氮治疗早产儿低氧性呼吸衰竭的初步研究

目的观察吸入一氧化氮（nitric oxide，NO）救治早产儿低氧性呼吸衰竭的安全性及有效性。方法两家三级医院新生儿重症监护病房2002年10月至2005年6月入住的胎龄小于35周早产儿，患呼吸窘迫综合征（respiratory distress syndrome，RDS）常规机械通气和（或）肺表面活性物质治疗2h后仍存在低氧性呼吸衰竭（FiO2≥0．4，PaO2〈50mm Hg，SpO2〈85％）者入选，分为常规治疗组（对照组，n=11）和吸入NO组（NO组，n=12）。监测肺动态顺应性（dynamic compliance，Cdyn）、气道阻力（airway resistance，RAW）、潮气量（tidal volume，VT）、氧合指数（oxygenation index，OI）和动脉血氧分压／肺泡氧分压（arterial—to-alveolar partial pressure of oxygen，a／A）。结果在治疗起始时NO组OI值（26．9±11．2）较对照组（13．7±6．5）高（P〈0．05），在治疗1h两组间差异无统计学意义，并保持至治疗72h（P〉0．05）。NO组OI值随治疗时间延长而不断降低；而对照组OI值在各时间点差异均无统计学意义。NO组起始a／A（0．08±0．03）较对照组（0．13±0．03）低（P〈0．01），两组a／A值逐渐升高，在治疗1h后两组间差异无统计学意义，直到治疗72h。NO组和对照组1、6、12、24、48、72h与0h相比，a／A值在1h起即比0h升高，到48h差异出现统计学意义（P〈0．05），并直至72h。吸入NO并未增加颅内出血、肺出血和慢性肺疾病的发生率。结论RDS早产儿吸入NO可能改善氧合和气体交换，且并未增加不良反应的发生，为多中心大样本随机对照研究提供了实验依据。     

Inhaled nitric oxide therapy in neonatal hypoxic respiratory failure: insights beyond primary outcomes

The Neonatal Research Network developed and initiated 3 multicenter randomized controlled clinical trials evaluating inhaled nitric oxide therapy. Additional projects evolved from these efforts including basic science research and observational investigations. This article provides a historical prospective of the Network's investigations related to the diagnosis and management of neonatal hypoxic respiratory failure, especially those related to inhaled nitric oxide therapy. It will review the Network's contributions toward advancing the clinical care of the newborn with severe hypoxic respiratory failure.     

Nitric oxide mediates inhibitory effect of interleukin-1beta on estrogen production in human granulosa-luteal cells

OBJECTIVE: To investigate the effect of IL-1beta on NO production and steroidogenesis in human granulosa-luteal cells obtained from women undergoing in vitro fertilization procedures. SUBJECTS AND METHODS: To investigate the effect of IL-1beta, granulosa-luteal cells were cultured with various doses of IL-1beta (0, 0.05, 0.5, 5, 50, 100 ng/ml), IL-1beta (5 ng/ml) with NG-nitro-L-arginine-methyl ester (L-NAME), selective inhibitors of NOS, sodium nitroprusside (SNP), NO donors and Genistain, a tyrosine kinase inhibitor. RESULTS: IL-1beta induced a dose-dependent stimulation of NO production and inhibited the production of estradiol in a significant way in a dose-dependent manner. L-NAME significantly decreased NO production and increased the production of estradiol and progesterone. SNP significantly increased NO production and caused decreases in the production of both estradiol and progesterone. Genistain decreased NO production and significantly increased the production of estradiol and progesterone. Inducible NOS (iNOS) messenger RNA was present in granulosa-luteal cells before treatment with IL-1beta. CONCLUSIONS: IL-1beta stimulated NO production, and NO inhibited the production of estradiol.     

Nitric oxide metabolite levels in preterm labor

AIM: To investigate the role of nitric oxide metabolites as markers of infection in subjects with preterm labor or preterm premature rupture of membranes (PTPROM). PTPROM means that there was spontaneous rupture of fetal membrane before the onset of labor and gestational age was <37 weeks. This occurs because of imbalance between matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase. The cause of this imbalance that leads to degradation of collagen causing PTPROM is infection. The bactericidal, fungicidal, viricidal and tumoricidal activities of macrophages are determined in part by elaboration of nitric oxide, hence nitric oxide levels have been found to be increased in infections. METHODS: During an 18-month period 50 women with preterm labor or PTPROM and 50 controls were enrolled prospectively. Blood and urine samples were obtained for analysis of nitric oxide metabolites. Patients with known causes of preterm labor were excluded. RESULT: The nitric oxide metabolites, which included both nitrite levels and citrulline levels were significantly higher both in blood as well as urine in patients with preterm labor and PTPROM compared to controls. Serum nitrite levels in subjects with preterm labor were 376.5 +/- 345 nmol/L while in subjects with PTPROM they were 295.7 +/- 161.1 nmol/L and in controls the levels were 62.7 +/- 33.9 nmol/L. Serum citrulline levels in subjects with preterm labor were 5293.8 +/- 2916.7 nmol/L; in PTPROM they were 6536.6 +/- 609.91 nmol/L and in controls they were 949.8 +/- 67.1 nmol/L. On comparing patients with preterm labor, those in whom preterm labor could not be inhibited had statistically significant higher levels of nitrite in both serum and urine (482.9 +/- 387.7 nmol/L and 754.5 +/- 336.5 nmol/L, respectively) compared to patients in whom labor could be inhibited (172.2 +/- 61.9 nmol/L and 401.8 +/- 236.9 nmol/L, respectively). The citrulline levels were also higher among the group who delivered preterm for both serum and urine (5355.4 +/- 3229.7 nmol/L and 11 482.8 +/- 2541.4 nmol/L, respectively) compared to patients in whom labor could be inhibited (5260.2 +/- 2897.08 nmol/L and 10 651.4 +/- 1502.7 nmol/L, respectively) but this did not reach statistical significance. CONCLUSION: Higher nitric oxide metabolites in women with preterm labor are marker of subclinical infection.     

Nitric oxide in the uteroplacental, fetoplacental, and peripheral circulations in preeclampsia.

OBJECTIVE: Altered production of nitric oxide by the vascular endothelium may influence the pathogenesis of preeclampsia. The aim of this study was to measure circulating levels of nitric oxide metabolites (nitrites) in the uteroplacental, fetoplacental, and peripheral circulation of preeclamptic pregnancies compared with normotensive controls. METHODS: Fifteen women with preeclampsia were compared with 16 women with normotensive pregnancies. At cesarean, blood samples were taken from the uterine vein draining the placental site, the umbilical vein, and the antecubital vein after delivery of the baby but before delivery of the placenta. Plasma nitrites were measured using the Greiss reaction after conversion of plasma nitrates to nitrites using nitrate reductase. RESULTS: Nitric oxide metabolites were higher in the uteroplacental (P < .01), fetoplacental (P < .001), and peripheral (P < .02) circulations in samples from preeclamptic pregnancies compared with control pregnancies. In samples from the fetoplacental circulation only, nitric oxide metabolite levels were negatively correlated with gestational age (r = -.489, P < .01) and birth weight (r = -.544, P < .004). Nitric oxide metabolite levels were not significantly correlated with blood pressure, placental weight, or maternal age. CONCLUSION: In established preeclampsia, production of nitric oxide was higher in the uteroplacental, fetoplacental, and peripheral circulation than in normotensive pregnancies. This increase may be part of a compensatory mechanism to offset the pathologic effects of preeclampsia.