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Spontaneous permanent DA closure occurs in >34% of ELBW neonates and is predicted by variables related to maturation, for example, EGA and an absence of HMD, whereas indomethacin failure could not be predicated.

Estradiol-17 ␤ (E 2 ␤ ), a potent vasodilator, has its greatest effects on the uterine vasculature, blood flow (UBF) increasing Ն 10-fold. The mechanism(s) responsible for E 2 ␤ -induced vasodilation is unclear. We determined if nitric oxide (NO)-induced increases in cGMP modulate estrogen-induced increases in UBF, and if cyclooxygenase inhibition modifies E 2 ␤ responses. Nonpregnant ( n ϭ 15) and pregnant ( n ϭ 8) ewes had flow probes implanted on main uterine arteries and catheters in branches of the uterine vein and artery bilaterally for blood sampling and infusion of the NO synthase inhibitor L -nitro-arginine methyl ester ( L -NAME), respectively. In nonpregnant ewes E 2 ␤ (1 g/kg) caused parallel increases ( P Ͻ 0.001) in UBF (15 Ϯ 3 to 130 Ϯ 16 ml/ min) and uterine cGMP secretion (23 Ϯ 10 to 291 Ϯ 38 pmol/ min); uterine venous cGMP also rose (4.98 Ϯ 1.4 to 9.43 Ϯ 3.2 pmol/ml; P Ͻ 0.001). Intra-arterial L -NAME partially inhibited increases in UBF dose-dependently (r ϭ 0.66, n ϭ 18, P Յ 0.003) while completely inhibiting cGMP secretion ( P ϭ 0.025). Indomethacin, 2 mg/kg intravenously, did not alter E 2 ␤ -induced responses. After E 2 ␤ -induced increases in UBF, intraarterial L -NAME partially decreased UBF dose dependently (r ϭ 0.73, n ϭ 46, P Ͻ 0.001) while inhibiting cGMP secretion (178 Ϯ 48 to 50 Ϯ 24 pmol/min; n ϭ 5, P ϭ 0.006); both were reversed by L -arginine. In pregnant ewes, E 2 ␤ increased UBF and venous cGMP (9.1 Ϯ 0.96 to 13.2 Ϯ 0.96 pmol/ml, P Ͻ 0.01); however, intraarterial L -NAME decreased basal cGMP secretion 66% (P ϭ 0.02), but not UBF. Acute estrogen-induced increases in UBF are associated with NO-dependent increases in cGMP synthesis, but other mechanisms may also be involved. However, vasodilating prostanoids do not appear to be important. In ovine pregnancy NO is not essential for maintaining uteroplacental vasodilation. ( J. Clin. Invest. 1996. 98:2158-2166.)

Estrogen (E) has nitric oxide (NO)-mediated effects in certain vascular beds, and fetal E levels rise acutely with parturition, suggesting that E may be involved in NO-mediated pulmonary vasodilation at birth. We tested the hypothesis that E acutely stimulates NO synthase (NOS) activity in ovine fetal pulmonary artery endothelial cells (PAEC) by measuring L-[3H]arginine conversion to L-[3H]citrulline in intact cells. NOS activity in the presence of 17 beta-estradiol (E2 beta) rose in a dose-dependent manner, increasing 70-100%, with a threshold concentration of 10(-10) M. This effect was detectable within 5 min of E2 beta exposure, and the maximal response was comparable to that obtained with acetylcholine, which had a threshold concentration of 10(-8) M. Ca2+ removal completely inhibited E2 beta-stimulated NOS activity, and activity with E2 beta and the Ca2+ ionophore A-23187 was not additive. In addition, the expression of the endothelial isoform of NOS (eNOS) was not altered, and the inducible and neuronal NOS isoforms were not detected by immunoblot analysis. These findings indicate that E2 beta acutely stimulates eNOS by Ca2+ influx. Furthermore, E2 beta-stimulated NOS activity was fully inhibited by the E receptor (ER) antagonists tamoxifen and ICI-182,780, and ER mRNA expression was evident in reverse transcription-polymerase chain reaction assays. Thus E acutely stimulates eNOS activity in fetal PAEC via the activation of endothelial ER and increases in intracellular Ca2+.

Objective To evaluate serum neuronal and inflammatory biomarkers to determine whether measurements of umbilical cords at birth can stratify severity of hypoxic-ischemic encephalopathy (HIE), whether serial measurements differ with hypothermia-rewarming, and whether biomarkers correlate with neurological outcomes. Study design This is a prospective cohort of inborn term newborns with varying degrees of HIE by neurological assessment. Neuronal glial fibrillary acidic protein (GFAP), ubiquitin carboxyl-terminal hydrolase L1, and inflammatory cytokines were measured in serum from umbilical artery at 6–24, 48, 72, and 78 hours of age. Neurodevelopmental outcomes (Bayley Scales of Infant and Toddler Development-III scales) were performed at 15–18 months. Results Twenty neonates had moderate (n = 17) or severe (n = 3) HIE and received hypothermia; 7 had mild HIE and were not cooled. At birth, serum GFAP and ubiquitin carboxyl-terminal hydrolase L1 increased with the severity of HIE (P < .001), and serial GFAP remained elevated in neonates with moderate to severe HIE. Interleukin (IL)-6, IL-8, and vascular endothelial growth factor were greater at 6–24 hours in moderate to severe vs mild HIE (P < .05). The serial values were unaffected by hypothermia-rewarming. Elevated GFAP, IL-1, IL-6, IL-8, tumor necrosis factor, interferon, and vascular endothelial growth factor at 6–24 hours were associated with abnormal neurological outcomes. Conclusions The severity of the hypoxic-ischemic injury can be stratified at birth because elevated neuronal biomarkers in cord serum correlated with severity of HIE and outcomes.