endothelin-1 and Infant--Premature--Diseases

Necrotizing enterocolitis (NEC) continues to be a devastating inflammatory disease of the newborn intestine. Despite advances in management, morbidity and mortality remain high. While it is clear that intestinal ischemia plays a large role in disease pathogenesis, attempts to link NEC to intestinal macrovascular derangement have been largely unsuccessful. More recently, there has been a concerted effort to characterize the pathologic changes of the intestinal microcirculation in response to intestinal injury, including NEC. This microcirculatory regulation is controlled by a balance of vasoconstrictor and vasodilator forces. Vasoconstriction is mediated primarily by endothelin-1 (ET-1), while vasodilation is mediated primarily by nitric oxide (NO). These chemical mediators have been implicated in many aspects of intestinal ischemic injury and NEC, with the balance shifting toward increased vasoconstriction associated with intestinal injury. With a proper understanding of these antagonistic forces, potential therapeutic avenues may result from improving this pathologic microcirculatory dysregulation.

Topics: Biomarkers; Endothelin-1; Enterocolitis, Necrotizing; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Intestines; Ischemia; Microcirculation; Nitric Oxide; Vasoconstriction; Vasodilation

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

We measured exhaled nitric oxide and tracheal aspirate endothelin-1 to determine relationships between these substances and alterations in pulmonary gas exchange during respiratory distress syndrome (RDS) in comparison to those obtained from control preterm infants without RDS. Eight infants with RDS had measurements made at 24 hr and again at 48-72 hr. Eight control infants were studied once at 24-48 hr of life. Exhaled gas was analyzed on-line, and minute excretion of NO (V(NO)) was calculated. ET-1 was determined by immunoassay. Median V(NO) at 24 hr in RDS was 0.405 nl/min/kg (range, 0.30 -0.79), which subsequently declined by 48-72 hr to 0.166 nl/min/kg (P < 0.01). The V(NO) in RDS infants was significantly higher than time-matched V(NO) in controls, with a median of 0.099 nl/min/kg (range, 0.03-0.27; P < 0.001). ET-1 was not correlated with initial V(NO) in the RDS or control patients. In conclusion, in RDS, V(NO) decreases as gas exchange improves. ET-1 is detectable in tracheal aspirate samples in both groups of infants.

Topics: Body Fluids; Breath Tests; Endothelin-1; Humans; Infant, Newborn; Infant, Premature, Diseases; Intubation, Intratracheal; Nitric Oxide; Pulmonary Surfactants; Reference Values; Respiratory Distress Syndrome, Newborn; Respiratory Function Tests; Trachea

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 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

The peptide endothelin-1 (ET-1) plays an unknown role in the pathogenesis and progression of two important neonatal pulmonary disorders, chronic lung disease (CLD) of prematurity and persistent pulmonary hypertension of the newborn (PPHN). Inhaled nitric oxide (INO) is a proven vasodilator therapy in PPHN and is an experimental therapy in CLD. We sought to determine the effects, if any, of the interaction of inhaled INO with ET-1 in these two separate disorders. Infants (n=21) with PPHN (mean gestation age, 39.4 weeks; mean birth weight, 3470 g) were treated with INO. All infants were <72 h of age at baseline. Plasma obtained at baseline and after 24 h of INO therapy was assessed for ET-1. The change in ET-1 levels with INO was inversely correlated with change in arterial partial pressure of O(2) (r=-0.71, P=0.0003). A separate group of 33 patients with CLD (mean gestational age, 27 weeks; mean birth weight, 740 g; mean age, 19 days) had tracheal aspirate levels of ET-1 obtained before, during, and after 7 days' administration of INO. Values were normalized by soluble secretory component of IgA. Tracheal aspirate ET-1 levels were detectable before INO therapy. There was no significant change during or after treatment with INO. There was not a significant correlation between baseline fractional inspired O(2) and ET-1 levels. There was a non-significant trend in the correlation between the change in ET-1 and the change in interleukin-8 levels in tracheal aspirate. This report confirms the presence of ET-1 in tracheal aspirate of premature infants who are developing CLD and reaffirms the presence of ET-1 in plasma of infants with PPHN. Short-term INO therapy was associated with a decrease in plasma ET-1 levels in PPHN, but did not affect tracheal aspirate ET-1 in CLD. Given the vasconstrictive, profibrotic, and proinflammatory properties of ET-1, specific ET-1 receptor antagonists could be considered as candidates for trials as adjunct therapy in either or both of these disorders.

Topics: Administration, Inhalation; Biomarkers; Endothelin-1; Humans; Hypertension, Pulmonary; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Interleukin-8; Nitric Oxide; Persistent Fetal Circulation Syndrome; Pulmonary Disease, Chronic Obstructive