Adrenomedullin is increased in the fetoplacental circulation in intrauterine growth restriction with abnormal umbilical artery waveforms (original) (raw)
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American Journal of Obstetrics and Gynecology, 2000
This study was undertaken to determine whether adrenomedullin, a hypotensive peptide, decreases vasomotor tone in fetoplacental vasculature that has been constricted with the thromboxane sympathomimetic U46619. STUDY DESIGN: The fetoplacental vascular beds of 20 perfused human placental cotyledons were vasoconstricted with a continuous infusion of U46619 (10-8 mol/L). The vasculature was then sequentially injected with deionized water, 30 ng adrenomedullin, 300 ng adrenomedullin, and 3000 ng adrenomedullin. Any change in perfusion pressure was noted after each dose. In a separate experiment the fetoplacental vasculature in 2 perfused cotyledons from each of 10 placentas was vasoconstricted with U46619 (10-8 mol/L). Adrenomedullin was infused continuously at either 200 ng/min (n = 5) or 2000 ng/min (n = 5) for 40 minutes. A corresponding control cotyledon from each placenta had isotonic sodium chloride solution added to its perfusion. Perfusion pressures were recorded every minute during the infusion and for 40 minutes afterward. Analysis of variance was used to compare pressure changes in the cotyledons that received bolus doses of adrenomedullin. Paired t tests of mean percentage pressure changes were used to compare the study and control groups that received the continuous infusions. RESULTS: In the cotyledons that received bolus doses of adrenomedullin, the mean (±SEM) percentage perfusion pressure changes from the baseline were-6.7 ± 0.5 for 30 ng adrenomedullin (P = .0039),-8.5 ± 0.7 for 300 ng adrenomedullin (P < .0001), and-13.1 ± 1.0 for 3000 ng adrenomedullin (P < .0001). With the continuous adrenomedullin infusion of 200 ng/min, there was no significant difference in the mean percentage pressure change from baseline between the study and control groups (-0.57%). At 2000 ng/min there was a significant difference (-15.34%; P < .0001). CONCLUSION: Adrenomedullin caused vasodilatation of fetoplacental vasculature previously constricted with the thromboxane sympathomimetic U46619 in the isolated perfused placental cotyledon. This vasodilatation occurred in a dose-dependent manner.
Ultrasound in Obstetrics and Gynecology, 2000
Objective To investigate adrenal artery blood flow in the fetus. Design and method Sixty-two appropriate-for-gestational-age (AGA) and 20 intrauterine growth-restricted (IUGR) fetuses were recruited to this cross-sectional study between 22 and 42 weeks of pregnancy in a tertiary referral fetal medicine unit of a university hospital. Endpoints Doppler velocimetry of the fetal adrenal, umbilical (UA), renal and middle cerebral arteries (MCA). Pulsatility index (PI), resistance index (RI), peak systolic velocity (PSV), time-averaged maximum velocity (TAMXV) and cerebroplacental ratio (MCA RI/UA RI; CPR). Obstetric outcome. Results The adrenal artery was detected in 82% of the fetuses. All flow velocity waveforms obtained from the adrenal artery indicated low impedance blood flow. No significant changes in PI, RI, PSV and TAMXV occurred with advancing gestation. The blood flow parameters of the adrenal artery did not differ between AGA and IUGR fetuses. In five IUGR fetuses with signs of redistribution of cardiac output in favor of the brain, the adrenal artery velocimetry results were unremarkable. The adrenal artery PI, RI, PSV and TAMXV values were higher in female fetuses than in male fetuses (P , 0.05). A relationship was observed between the velocity measurements and the estimated fetal weight (P , 0.01). Conclusions The fetal adrenal artery could be readily detected. We observed no redistribution of blood flow in favor of the fetal adrenals in IUGR fetuses which were not severely compromised.
Adrenomedullin in perinatal medicine
Regulatory Peptides, 2003
This review will consider whether adrenomedullin (AM) plays a role in the different aspects of perinatal medicine: contributing to maternal systemic vasodilatation during pregnancy, regulating uterine and placental blood flow, being involved in the process of implantation and participating in uterine quiescence prior to parturition. In addition, this will also consider whether a modification of AM secretion contributes to some pathological conditions in pregnancy such as preeclampsia and impairment of fetal growth. The biosynthesis of AM increases in gravid rats and in pregnant women, and the placenta represents an important site of AM production during pregnancy. Both the peptide and its receptors have been found in the uterus, placenta, fetal membranes and cord vessels, and fetal membranes and placental tissues in culture secrete AM. AM contributes to maternal systemic vasodilatation, the placental vessels are relaxed by AM in a dose-dependent manner and AM is expressed in the fetoplacental and umbilical vascular endothelium where basal production of AM contributes to low fetoplacental vascular resistances. Controversy exists over the status of circulating and placental AM in preeclampsia and of the relative contribution of AM to impaired fetoplacental circulation and fetal growth. Moreover, the uterus expresses AM mRNA and exogenous AM relaxes the myometrium in a dose-dependent manner; however, clinical studies have shown that AM does not decrease before the onset of parturition. Rather, AM secretion increases during spontaneous labor and in preterm delivery.
Vascular expression of adrenomedullin is increased in Wistar rats during early pregnancy
European Journal of Obstetrics & Gynecology and Reproductive Biology, 2005
Objective: Circulating levels of adrenomedullin (ADM)-a vasodilator peptide with long-lasting effects-increase in the course of pregnancy. Neither the site nor the concomitant rate of ADM synthesis in pregnancy is known. The aim of this study was to test the hypothesis that the rise in plasma levels of ADM during pregnancy is paralleled by increased gene expression and protein levels in the vascular bed. Study design: We determined in cardiovascular and reproductive tissues of non-pregnant (n = 10) and 10-days pregnant (n = 10) Wistar rats ADM gene expression by semi-quantitative RT-PCR (normalized to GAPDH). As a support for the mRNA data, protein concentrations were measured by both ELISA and Western blot analysis. Finally, ADM in these tissues was localized by immunohistochemical staining. Statistical analysis was carried out by applying Mann-Whitney U-test. Results: ADM mRNA levels in the abdominal aorta, renal artery and the kidney were increased during pregnancy. In addition, immunohistochemical staining in the kidney, uterus, abdominal aorta, renal, uterine and superior mesenteric artery was more intense as compared to non-pregnant rats. However, we observed lower concentrations of tissue ADM protein in pregnant rats, indicating an increased release of the hormone by the producing cells. Conclusion: Vascular ADM gene expression is increased in the first half of rat pregnancy. This coincides and may be functionally related to the institution of a high flow/low resistance circulation in pregnancy. #
Detection of adrenomedullin, a hypotensive peptide, in amniotic fluid and fetal membranes
American Journal of Obstetrics and Gynecology, 1996
OBJECTIVE: Our purpose was to determine whether adrenomedullin, a multifunctional regulatory peptide involved in blood flow regulation and growth stimulation and with antimicrobiai activity, was a component of amniotic fluid from second-trimester human fetus and to determine the source of this peptide. STUDY DESIGN: A prospective descriptive study was performed on 134 patients undergoing amniocentesis after genetic counseling, ultrasonography, and infomed consent. Adrenomedullin expression was determined by immunocytochemical analysis, Western blot analysis, reverse transcriptase-polymerase chain reaction, and in situ reverse transcriptase-polymerase chain reaction in fetal membranes and with radioimmunoassay in amniotic fluid. RESULTS: Radioimmunoassay of the 134 amniotic fluid specimens revealed adrenomedullin-like immunoreactivJty in all of them, ranging in concentration from 10 to 300 fmol/25 gl (170 _+ 62 fmol/25 gl). Immunocytochemical analysis, Western blot analysis, reverse transcriptase-polymerase chain reaction, and in situ reverse transcriptase-polymerase chain reaction further established the expression of adrenomedullin protein and messenger ribonucleic acid in fetal amniotic membranes, suggesting that this organ is the source of amniotic adrenomedullin. CONCLUSIONS; Our results clearly demonstrate the presence of adrenomedullin in second-trimester human amniotic fluid and adrenomedullin messenger ribonucleic acid and protein in amniotic membranes, suggesting that adrenomedullin is a hormone involved in the maintenance of normal pregnancy. Further studies with these molecular tools are in progress to determine the precise role of this hormone and whether adrenomedullin plays a role in the pathogenesis of various disorders of pregnancy. (Am J Obstet Gynecol 1996;175:906-11 .)
Adrenomedullin, a New Vasoactive Peptide, Is Increased in Preeclampsia
Hypertension, 1998
Adrenomedullin is a novel peptide that elicits a long-lasting vasorelaxant activity. Recently, we found high concentrations of adrenomedullin in maternal and umbilical cord plasma and in amniotic fluid in full-term human pregnancy, indicating a role of this peptide during gestation. To investigate the possibility that adrenomedullin is involved in the pathophysiology of preeclampsia, we measured its concentration in maternal and fetoplacental compartments. We studied 12 normotensive nonpregnant women, 13 hypertensive nonpregnant subjects, 29 patients with preeclampsia, and 30 normotensive pregnant women. In all patients, plasma was collected from the cubital vein, and amniotic fluid samples were obtained by transabdominal amniocentesis or at elective cesarean section. Plasma samples from umbilical vein and placental tissues were collected at delivery. Adrenomedullin was assayed on plasma and amniotic fluid samples using a specific radioimmunoassay, and its localization and distribution on placental sections was determined by immunohistochemistry. Adrenomedullin concentrations were higher in hypertensive than in normotensive nonpregnant patients. Pregnant women had higher adrenomedullin levels than nonpregnant subjects, although maternal plasma adrenomedullin concentrations did not differ between normal pregnant and preeclamptic women. Preeclamptic patients showed higher concentrations (PϽ0.01) than normotensive pregnant women of adrenomedullin in amniotic fluid (252Ϯ29 versus 112Ϯ10 fmol/mol creatinine) and umbilical vein plasma (18.1Ϯ2.1 versus 8.5Ϯ1.1 fmol/mL). Increased local production of adrenomedullin is associated with preeclampsia. The fetus seems to be responsible for the higher levels of this hormone. Increased adrenomedullin concentrations may be necessary to maintain placental vascular resistance and/or fetal circulation at a physiological level. (Hypertension.
Elevated endothelin levels are associated with increased placental resistance
American Journal of Obstetrics and Gynecology, 1996
The purpose of this study was to measure cord blood endothelin-l,2 concentrations in growth-restricted infants with abnormal flow velocity waveforms. STUDY DESIGN: Endothelin-1,2 concentrations were measured by radioimmunoassay in the cord blood of 16 growth-restricted infants with abnormal flow velocity waveforms before delivery, 16 growth-restricted infants with normal flow velocity waveforms before delivery, and 44 appropriately grown infants. Clinical data regarding pregnancy complications and neonatal outcome were collected. RESULTS: The mean endothelin-1,2 concentration in growth-restricted infants with abnormal flow velocity waveforms (50.2 + 16.4 pg/ml) was significantly higher than in growth-restricted infants with normal flow velocity waveforms (33.3 + 14.2 pg/ml, p < 0.05) or in appropriately grown infants (25.8 _+ 9.7 pg/ml, p < 0.05). Oligohydramnios was also associated with elevated endothelin levels. CONCLUSION: We conclude that endothelin-1,2 concentrations are elevated in growth-restricted infants with abnormal flow velocity waveforms and may play a role in the development of abnormal fetoplacental resistance. (AM J OBSTET GYNECOL 1996;174:1599-604.) Key words; Endothelin, fetal growth restriction, umbilical velocimetry, oligohydramnios Umbilical artery flow velocity waveforms are commonly used in the antenatal evaluation of high-risk fetuses. Decreased to absent end-diastolic flow velocities, reflecting increased vascular resistance in the fetoplacental unit, are associated with intrauterine growth restriction (IUGR), pregnancy-induced hypertension, and fetal distress necessitating delivery, but the etiology of this increased vascular resistance is not completely understood.
Labour-associated changes in adrenomedullin content in human placenta and fetal membranes
Clinical Science, 2003
The aim of the present study was to determine the effects of labour and mode of delivery on human placental and fetal membrane content of adrenomedullin (AdM). Placentas and fetal membranes were collected either at term or pre-term gestation from women either in labour or not in labour, and AdM was measured in tissue extracts by specific RIA. There were significant increases in AdM concentrations in amnion and choriodecidua for the in-labour group compared with the not-in-labour group for both pre-term and term gestations. There was no difference in AdM concentration in placental tissue between labour groups. This study provides evidence that fetal membrane AdM is increased in amniotic and choriodecidual tissues in response to labour, and suggests that it may play a role during human labour.
Diagnostics
Corticoids are largely used for fetal interest in expected preterm deliveries. This study went further, evaluating the effect of maternal administration of dexamethasone (Dex) on the umbilical artery (UA), middle cerebral artery (MCA), and ductus venous (DV) spectrum, in growth-restricted fetuses, with the absent end-diastolic flow (AEDF) in UA, from singleton early-onset severe preeclamptic pregnancies. Supplementary, the impact on both uterine arteries (UTAs) flow was also evaluated. In 68.7% of cases, the EDF was transiently restored (trAEDF group), in the rest of 31.2% remained persistent absent (prAEDF group). UA-PI significantly decreased in the first day after Dex (day 1/0; p < 0.05), reaching its minimum during day 2 (day 2/1; p > 0.05), revealing a significant recovery to day 4 (day 4/2; p < 0.05), in both groups. The MCA-PI decreased from day 1 until day 3 in both groups, but significantly only in the trAEDF group (p = 0.030 vs. p = 0.227. The DV-PI’s decrease (du...
American Journal of Obstetrics and Gynecology, 2004
Objective: Our aim was to study the hemodynamic effects of betamethasone on fetuses with intrauterine growth restriction (IUGR) with absent or reversed end-diastolic (ARED) umbilical artery flow. Study design: Color/pulsed Doppler waveforms were obtained before and after intramuscular injections of betamethasone in 19 consecutive fetuses with IUGR/ARED and 6 control fetuses. Peak velocities and pulsatility index (PI) values were obtained from the umbilical (UA) and middle cerebral (MCA) arteries and intrahepatic umbilical vein (UV). Results: Ten ARED fetuses developed transient positive umbilical end-diastolic flow after steroids, whereas nine fetuses showed persistent ARED. The persistent ARED subgroup demonstrated increased UA and UV peak velocities after steroids, which may indicate fetal hypertension. Fetal death (n = 2) and severe acidosis (n = 2) were confined to the subgroup with persistent ARED. Conclusion: Preterm IUGR/ARED fetuses exhibit divergent cardiovascular responses to prenatal steroids. Intensive Doppler-based fetal monitoring may identify a subset of fetuses prone to decompensation after maternal steroid administration.