Normal amino-terminal pro-brain natriuretic peptide (NT-proBNP) values in amniotic fluid.

INTRODUCTION: Brain natriuretic peptide (BNP) is synthesized by human fetal membranes, both the amnion and chorion. This locally produced BNP inhibits the contraction of the human myometrium, contributing to the maintenance of myometrial quiescence during pregnancy. Reference values for NT-proBNP concentrations in amniotic fluid at different gestational ages have not been completely defined. We aimed to investigate the range of fetal NT-proBNP values in amniotic fluid in normal pregnancy between 17 and 41weeks of gestation. METHODS: Samples of amniotic fluid were obtained from women meeting the following inclusion criteria: gestational age defined by early ultrasound, singleton gestation and not in labor. The exclusion criteria were as follows: multiple gestation, clinically evident chorioamnionitis, laboratory signs of infection in the amniotic fluid sample and fetal conditions that may alter NT Pro-BNP levels (anemia, hydrops, etc.). NT-proBNP concentrations in amniotic fluid were measured using the automated Elecsys® proBNP assay. RESULTS: We analyzed 218 samples of amniotic fluid at various gestational ages. Half of the samples were obtained by amniocentesis (118 samples), and the other half (100 samples) were obtained by direct puncture at the time of cesarean section. We found a significant decline in NT-proBNP concentrations with advancing gestational age. DISCUSSION: Gestational age has to be taken into consideration in the assessment of NT-proBNP values. Our data may be used as reference values in fetal medicine, as a possible predictor of preterm delivery risk using the inferior limit (0.5 multiples of the median (MoM)) of our normal curve.

The Synergic In Vitro Tocolytic Effect of Nifedipine Plus Ritodrine on Human Myometrial Contractility.

Many pharmacological agents have been investigated to manage preterm labor; we postulate that a combination of tocolytic drugs may achieve a better effect in the prevention of uterine contractions without dose-dependent adverse effects. The aim of this study was to evaluate the inhibitory effect of dual combinations of tocolytics in vitro. Human myometrium was obtained during elective cesarean sections (term without labor; n = 40). Myometrial strips were placed in organ baths for the measurement of isometric tension. Contractile activity was induced by oxytocin (10-8 mol/L), then a concentration-response curve to single or dual combinations of tocolytics was started. All studied tocolytics (nifedipine, ritodrine, nitroglycerin, atosiban, and NS-1619), when used alone, significantly inhibited myometrial contractions. When combined, nifedipine plus ritodrine produced a significantly greater inhibition of contractility than each drug alone in the midrange of concentrations. The combination of nifedipine plus nitroglycerin or nifedipine plus atosiban produced a significantly greater inhibition than nitroglycerin or atosiban alone but not greater than nifedipine. The combination of nifedipine plus NS-1619 (Ca+2-activated K+ [BKCa] channel opener) reduced the inhibitory effect of each drug. We concluded that a selected combination of tocolytics (nifedipine plus ritodrine) produced a significantly greater inhibitory effect on contractility than each drug alone at intermediate concentrations. Thus, specific combinations of tocolytics with different intracellular signaling pathways may have a synergic effect constituting a provocative new option for preterm labor treatment.

P2Y1 and P2Y2 receptor distribution varies along the human placental vascular tree: role of nucleotides in vascular tone regulation.

The expression of purinergic P2Y receptors (P2YRs) along the cord, superficial chorionic vessels and cotyledons of the human placenta was analysed and functional assays were performed to determine their vasomotor activity. Immunoblots for the P2Y(1)R and P2Y(2)R revealed a 6- to 8-fold increase in receptor expression from the cord to the chorionic or cotyledon vessels. In the cord and chorionic vessels the receptor distribution was mainly in the smooth muscle, whereas in the cotyledon vessels these receptors were equally distributed between the endothelium and smooth muscle cells. An exception was the P2Y(2)R at the umbilical artery, which was distributed as in the cotyledon. mRNA coding for the P2Y(1)R and P2Y(2)R were detected by RT-PCR and the mRNA coding for the P2Y(4)R, P2Y(6)R and P2Y(11)R was also identified. Application of 2-MeSADP and uridine triphosphate (UTP), preferential P2Y(1)R and P2Y(2)R ligands, respectively, resulted in contraction of isolated rings from umbilical and chorionic vessels. The vasoconstriction was blocked in a concentration-dependent manner by 10-100 nm indomethacin or 10 nm GR32191, suggesting the involvement of thromboxane receptors. MRS 2179, a selective P2Y(1)R antagonist, reduced the 2-MeSADP- but not the UTP-evoked contractions. Perfusion of cotyledons with 2-MeSADP or UTP evoked concentration-dependent reductions in perfusion pressure mediated by the NO-cGMP pathway. Blockade of NO synthase abolished the vasodilatation and the rise in luminal NO elicited by either agonist. MRS 2179 antagonized the dilatation and rise in luminal NO evoked by 2-MeSADP but not by UTP. In summary, P2Y(1)R and P2Y(2)R are unevenly distributed along the human placental vascular tree; both receptors are coupled to different signalling pathways in the cord/chorionic vessels versus the cotyledon leading to opposing vasomotor responses.

Modulator role of neuropeptide Y in human vascular sympathetic neuroeffector junctions.

Reverse transcription polymerase chain reaction (RT-PCR) studies identified the mRNA coding for the Y1 and Y2 receptors in human mammary artery/vein and saphenous vein biopsies. Y1 receptors are expressed in vascular smooth muscles and potentiate the contractile action of sympathetic co-transmitters, adenosine triphosphate (ATP) and noradrenaline (NA); BIBP 3226, a competitive Y1 receptor antagonist, blocked the neuropeptide Y (NPY)-induced modulation. The Y2 receptor is expressed in sympathetic nerves terminals and modulates the pool of sympathetic co-transmitters released at the neuroeffector junction. NPY plays a dual role as a modulator of sympathetic co-transmission; it facilitates vascular smooth muscle reactivity and modulates the presynaptic release of ATP and NA. Sympathetic reflexes regulate human vascular resistance, where NPY plays a modulator role of paramount importance following increased sympathetic discharges, such as stress and vascular disease.