Systemic and fetal–maternal nitric oxide synthesis in normal pregnancy and pre‐eclampsia

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Abstract
Objective To investigate systemic and fetal-placental nitric oxide synthesis by biochemical and molecular biology means in normal human pregnancy and pre-eclampsia. Design and participants 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. Setting Mario Negri Institute for Pharmacological Research, Bergamo, and the Division of Obstetrics and Gynaecology of the University of Brescia. Main outcome measures 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 α (TNFα) and in placenta homogenates incubated in calcium free medium. Results 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. Conclusions 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.
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