endothelin-1 and Ductus-Arteriosus--Patent

New insights into the closure of the ductus arteriosus may lead to more effective nonsurgical treatment in patent ductus arteriosus. ET-1 agonists may prove useful in future pharmacologic interventions.

Topics: Animals; Critical Care; Cytochrome P-450 Enzyme System; Ductus Arteriosus; Ductus Arteriosus, Patent; Endothelin-1; Humans; Infant, Newborn; Prostaglandins

Widened pulse pressure is a classic sign of significant left-to-right shunting patent ductus arteriosus (PDA), but little evidence supports this statement in the early life of premature infants with respiratory distress syndrome (RDS) needing nonsteroidal anti-inflammatory drugs (NSAIDs), the pharmacological treatment for PDA. Pulse pressure and urinary endothelin-1 (ET-1) and arginine vasopressin (AVP) vasoactive factors involved in the transitional circulation were measured before and after the NSAIDs treatment of 46 RDS premature infants receiving either ibuprofen (n = 22) or indomethacin (n = 24), with 28 responders and 18 nonresponders to the first NSAIDs course. We found that following pharmacological PDA closure, systolic and diastolic blood pressure significantly increased, maintaining a stable pulse pressure. However, when pharmacological closure failed, the trend (nonsignificant) was for a more consistent increase in systolic than in diastolic blood pressure, which determined a statistically significant widening pulse pressure. In addition, urinary ET-1 excretion rates decreased significantly after PDA closure, whereas persistent more aggressive pharmacological therapy failed. Urinary AVP excretion rates decreased insignificantly after therapy, uninfluenced by the efficacy of the drugs. We concluded that widened pulse pressure is a clinical sign of failed PDA pharmacological closure in RDS premature infants. ET-1 levels remain elevated when NSAIDs fail to interrupt left-to-right PDA shunting that complicates recovery from RDS.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Arginine Vasopressin; Blood Pressure; Ductus Arteriosus, Patent; Endothelin-1; Female; Humans; Ibuprofen; Indomethacin; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Male; Treatment Failure

The evaluation of the patent ductus arteriosus (PDA) in the very premature neonate is a challenge. Echocardiography provides an interpretation of the hemodynamic condition. It is however, only a snapshot. Biomarkers may represent a physiological response to the hemodynamic alterations brought on by the PDA and may add to the identification of the clinical significant PDA.. To investigate the association between mid regional proadrenomodulin (MR-proADM), N-terminal pro b-type natriuretic peptide (NT-proBNP), mid regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro endothelin-1 (CT-proET1) and copeptin and echocardiographic measures of PDA.. Cohort study with echocardiography performed on day 3 and 6. Blood samples from day 3.. 139 consecutive neonates born at a gestational age <32 weeks.. The main outcomes were presence of a PDA day 3 and 6, PDA diameter, left atrium to aorta ratio (LA:Ao-ratio), and descending aorta diastolic flow (DADF).. Adjusted plasma levels of all investigated biomarkers, except CT-proET1, were found to be associated with both PDA diameter and LA:Ao-ratio, and also the presence of a large PDA. CT-proET1 and copeptin was found to be associated with abnormal DADF. Using pre-specified cut-off values NT-proBNP and MR-proANP day 3 seemed to be of value in identifying a large PDA day 3 and 6 in very preterm neonates.. Among the investigated biomarkers NT-proBNP and MR-proANP performed best in relation to echocardiographic markers of PDA severity in very preterm neonates.

Topics: Adrenomedullin; Atrial Natriuretic Factor; Biomarkers; Ductus Arteriosus, Patent; Echocardiography; Electrocardiography; Endothelin-1; Female; Glycopeptides; Humans; Infant, Newborn; Infant, Premature; Male; Natriuretic Peptide, Brain

The diagnostic and prognostic appraisal of patent ductus arteriosus (PDA) in preterm infants is still debatable.. To compare plasma cardiovascular biomarkers with echocardiographic indices alongside ductus arteriosus (DA) evolution in very preterm infants within the first week of life.. Mid-regional pro-atrial natriuretic peptide (MR-proANP) and C-terminal pro-endothelin-1 (CT-proET-1) levels were prospectively measured on the second and sixth days of life (DOL) in 52 preterm infants born before 32weeks of gestation. Echocardiographic indices to define DA patency and significance were simultaneously obtained. Logistic regression and receiver operating characteristics (ROC) analyses were used to assess and quantify the biomarkers' diagnostic capacities.. Thirty infants exhibited PDA on DOL 2; in 21 of these infants, DA was characterized as hemodynamically significant. Treatment failure after a first course of indomethacin was noted in 8 infants (DOL 6), whereas 7 participants underwent later surgical ligation. The diagnostic accuracy of cardiovascular biomarkers was moderate on DOL 2 but high on DOL 6. PDA was the only significant predictor of MR-proANP levels on DOL 6, independent of the effect of clinical confounders (regression coefficient 0.426, R(2) 0.60). Infants with MR-proANP ≥850pmol/l on DOL 2 had 3.9-fold higher risk (95% CI 1.01 to 14.5) of being diagnosed with significant DA, whereas infants with MR-proANP ≥700pmol/l on DOL 6 had 7.1-fold higher risk (1.9 to 27.2) for pharmaceutical treatment failure.. The cardiovascular plasma biomarker MR-proANP is a promising candidate for monitoring PDA evolution in very preterm infants.

Topics: Atrial Natriuretic Factor; Biomarkers; Cross-Sectional Studies; Ductus Arteriosus, Patent; Endothelin-1; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Logistic Models; Prognosis; Prospective Studies; Treatment Outcome; Ultrasonography

In very preterm infants, clinical decision-making, such as closing a patent ductus arteriosus (PDA), may be aided by measuring circulating natriuretic and endothelial pro-peptides.. To investigate the association between perinatal characteristics, PDA echocardiography and plasma concentrations of stable pro-peptides of B-type natriuretic peptide (NT-proBNP), atrial natriuretic peptide (MR-proANP) and endothelin-1 (CT-proET-1).. A prospective, cross-sectional, single-center study was performed in 66 infants who were less than 32 weeks of gestational age. Pro-peptide concentrations were determined at birth and at day 2-3 of life.. Plasma concentrations of all 3 pro-peptides increased on average 2- to 5-fold from birth to day 2-3 of life. NT-proBNP and MR-proANP were closely related at birth and at day 2-3 (Rs 0.902 and 0.897, respectively, p < 0.001), whereas CT-proET-1 was related to NT-proBNP and MR-proANP at birth (Rs 0.478 and 0.460, respectively, p < 0.001) but not at day 2-3. Birth weight was negatively related to all 3 pro-peptides at birth (p < 0.01); however, preeclampsia and compromised placental perfusion were associated with elevated NT-proBNP and MR-proANP concentrations at birth. At day 2-3, MR-proANP and NT-proBNP correlated significantly with the ductal diameter (Rs 0.416 and 0.415, respectively, both p = 0.011), whereas CT-proET-1 correlated with the left atrium/aorta ratio (Rs 0.506, p = 0.027). CT-proET-1 was elevated in infants with treated compared to untreated PDA [median (5-95% range) 388 (272-723) vs. 303 (152-422) pmol/l, p = 0.011], but not NT-proBNP or MR-proANP.. CT-proET-1 is a promising predictor in determining the need for PDA intervention.

Topics: Atrial Natriuretic Factor; Ductus Arteriosus, Patent; Echocardiography; Endothelin-1; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Male; Natriuretic Peptide, Brain; Peptide Fragments; Placenta; Pre-Eclampsia; Pregnancy; Protein Precursors

The ductus arteriosus is a specialized blood vessel containing highly differentiated and contractile vascular smooth muscle, derived largely from neural crest cells, that is essential for fetal life but typically closes after birth. Impaired development of the ductus arteriosus or disruption of signaling pathways that initiate postnatal closure can result in persistent patency of the ductus arteriosus, the third most common congenital heart defect. We found that Tfap2beta, a transcription factor associated with patent ductus arteriosus in humans, was uniquely expressed in mouse ductal smooth muscle. Endothelin-1 and the hypoxia-induced transcription factor, Hif2alpha were also highly enriched in ductal smooth muscle at embryonic day 13.5 and were dependent on Tfap2beta for their expression in this domain. Hif2alpha functioned as a negative regulator of Tfap2beta-induced transcription by disrupting protein-DNA interactions, suggesting a negative feedback loop regulating Tfap2beta activity. Our data indicate that Tfap2beta, Et-1, and Hif2alpha act in a transcriptional network during ductal smooth muscle development and that disruption of this pathway may contribute to patent ductus arteriosus by affecting the development of smooth muscle within the ductus arteriosus.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Differentiation; Disease Models, Animal; Ductus Arteriosus; Ductus Arteriosus, Patent; Endothelin-1; Fetus; Humans; Mice; Mice, Knockout; Muscle, Smooth, Vascular; Mutation; Signal Transduction; Transcription Factor AP-2; Transcription, Genetic; Transfection

Topics: Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Ductus Arteriosus, Patent; Endothelin-1; Hemodynamics; Humans; Infant, Newborn; Infant, Premature; Ligation; Vasopressins

The relative potency and interrelationship between vasoactive and natriuretic mediators are thought to be important in the transition from fetal to neonatal life. The relationship between urinary vasoactive factors and sodium excretion has not been adequately addressed in premature infants receiving indomethacin and ibuprofen for therapy of patent ductus arteriosus. Excretion rates of AVP, ET-1 and sodium were measured in premature infants with RDS receiving indomethacin or ibuprofen. Forty-four RDS premature infants (<34-week gestation) with PDA received either ibuprofen (n=22) in an initial dose of 10 mg/kg followed by two doses of 5 mg/kg each after 24 and 48 h or 3 doses at 12-h intervals of indomethacin (n=24), 0.2 mg/kg, infused continuously over a period of 15 min. Urinary ET-1, AVP and sodium excretion were measured before and after treatment. Indomethacin treatment caused a significant decrease in urinary ET-1 and AVP excretion (UET-1/Ucr 0.14+/-0.01 vs. 0.10+/-0.05 fenton/mmol; P<0.05; 24.42+/-6.18 vs. 12.63+/-3.06 pg/mmol; P<0.05, respectively), along with a significant reduction in urinary sodium (92.1+/-36.1 vs. 64.8+/-35.6 mmol/l; P<0.01), fractional excretion of sodium (6.8+/-37.1 vs. 4.5+/-37.1%; P<0.01) and urinary osmolality (276.2+/-103.9 vs. 226.4+/-60.3 mOsmol/kg; P<0.05). Ibuprofen treatment caused a significant decrease in urinary AVP (UAVP/Ucr 24.5+/-3.4 vs. 16.3+/-2.04 pg/mmol; P<0.01), along with a significant decrease in urinary sodium (78.0+/-8.4 vs. 57.0+/-8.0 mmol/l; P<0.05) and in fractional excretion of sodium (7.5+/-1.3 vs. 3.9+/-3.0%; P<0.05), while it did not modify urinary ET-1 excretion. The association of renal ET-1 and AVP activity with sodium excretion in premature infants treated with indomethacin and ibuprofen supports the hypothesis that these factors may play a role in the physiologic changes in sodium excretion.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Arginine Vasopressin; Cyclooxygenase 2 Inhibitors; Ductus Arteriosus, Patent; Endothelin-1; Humans; Ibuprofen; Indomethacin; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Sodium

We studied tone in the human ductus arteriosus and show that the constriction to oxygen is due to inhibition of voltage-gated potassium channels and, in the acute phase, is independent of endothelin-1.

Topics: 4-Aminopyridine; Charybdotoxin; Cyclooxygenase Inhibitors; Ductus Arteriosus; Ductus Arteriosus, Patent; Endothelin-1; Glyburide; Humans; Hypoxia; Ion Channel Gating; Membrane Potentials; Muscle, Smooth, Vascular; Nitric Oxide Synthase; Oxygen Consumption; Potassium Channels