scholarly journals Apocynin improves oxygenation and increases eNOS in persistent pulmonary hypertension of the newborn

2012 ◽  
Vol 302 (6) ◽  
pp. L616-L626 ◽  
Author(s):  
Stephen Wedgwood ◽  
Satyan Lakshminrusimha ◽  
Kathryn N. Farrow ◽  
Lyubov Czech ◽  
Sylvia F. Gugino ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Nadph Oxidase ◽  
Ductus Arteriosus ◽  
Pulmonary Arteries ◽  
Oxidase Inhibitor ◽  
No Synthase ◽  
Persistent Pulmonary Hypertension ◽  
No Donor ◽  
Oxidase Inhibition ◽  
Endothelial Nitric Oxide

NADPH oxidase is a major source of superoxide anions in the pulmonary arteries (PA). We previously reported that intratracheal SOD improves oxygenation and restores endothelial nitric oxide (NO) synthase (eNOS) function in lambs with persistent pulmonary hypertension of the newborn (PPHN). In this study, we determined the effects of the NADPH oxidase inhibitor apocynin on oxygenation, reactive oxygen species (ROS) levels, and NO signaling in PPHN lambs. PPHN was induced in lambs by antenatal ligation of the ductus arteriosus 9 days prior to delivery. Lambs were treated with vehicle or apocynin (3 mg/kg intratracheally) at birth and then ventilated with 100% O2 for 24 h. A significant improvement in oxygenation was observed in apocynin-treated lambs after 24 h of ventilation. Contractility of isolated fifth-generation PA to norepinephrine was attenuated in apocynin-treated lambs. PA constrictions to NO synthase (NOS) inhibition with N-nitro-l-arginine were blunted in PPHN lambs; apocynin restored contractility to N-nitro-l-arginine, suggesting increased NOS activity. Intratracheal apocynin also enhanced PA relaxations to the eNOS activator A-23187 and to the NO donor S-nitrosyl- N-acetyl-penicillamine. Apocynin decreased the interaction between NADPH oxidase subunits p22phox and p47phox and decreased the expression of Nox2 and p22phox in ventilated PPHN lungs. These findings were associated with decreased superoxide and 3-nitrotyrosine levels in the PA of apocynin-treated PPHN lambs. eNOS protein expression, endothelial NO levels, and tetrahydrobiopterin-to-dihydrobiopterin ratios were significantly increased in PA from apocynin-treated lambs, although cGMP levels did not significantly increase and phosphodiesterase-5 activity did not significantly decrease. NADPH oxidase inhibition with apocynin may improve oxygenation, in part, by attenuating ROS-mediated vasoconstriction and by increasing NOS activity.

scholarly journals Increased superoxide production contributes to the impaired angiogenesis of fetal pulmonary arteries with in utero pulmonary hypertension

2009 ◽  
Vol 297 (1) ◽  
pp. L184-L195 ◽  
Author(s):  
Ru-Jeng Teng ◽  
Annie Eis ◽  
Ivane Bakhutashvili ◽  
Nandini Arul ◽  
Girija G. Konduri
Keyword(s):  
Oxidative Stress ◽  
Pulmonary Hypertension ◽  
Nadph Oxidase ◽  
Ductus Arteriosus ◽  
Pulmonary Arteries ◽  
Tube Formation ◽  
Oxidase Inhibitor ◽  
Superoxide Production ◽  
Mrna Levels ◽  
Impaired Angiogenesis

Persistent pulmonary hypertension of newborn (PPHN) is associated with impaired pulmonary vasodilation at birth. Previous studies demonstrated that a decrease in angiogenesis contributes to this failure of postnatal adaptation. We investigated the hypothesis that oxidative stress from NADPH oxidase (Nox) contributes to impaired angiogenesis in PPHN. PPHN was induced in fetal lambs by ductus arteriosus ligation at 85% of term gestation. Pulmonary artery endothelial cells (PAEC) from fetal lambs with PPHN (HTFL-PAEC) or control lambs (NFL-PAEC) were compared for their angiogenic activities and superoxide production. HTFL-PAEC had decreased tube formation, cell proliferation, scratch recovery, and cell invasion and increased cell apoptosis. Superoxide (O2−) production, measured by dihydroethidium epifluorescence and HPLC, were increased in HTFL-PAEC compared with NFL-PAEC. The mRNA levels for Nox2, Rac1, p47phox, and Nox4, protein levels of p67phox and Rac1, and NADPH oxidase activity were increased in HTFL-PAEC. NADPH oxidase inhibitor, apocynin (Apo), and antioxidant, N-acetyl-cysteine (NAC), improved angiogenic measures in HTFL-PAEC. Apo and NAC also reduced apoptosis in HTFL-PAEC. Our data suggest that PPHN is associated with increased O2− production from NADPH oxidase in PAEC. Increased oxidative stress from NADPH oxidase contributes to the impaired angiogenesis of PAEC in PPHN.

Decreased association of HSP90 impairs endothelial nitric oxide synthase in fetal lambs with persistent pulmonary hypertension

2003 ◽  
Vol 285 (1) ◽  
pp. H204-H211 ◽  
Author(s):  
Girija G. Konduri ◽  
Jingsong Ou ◽  
Yang Shi ◽  
Kirkwood A. Pritchard
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Ductus Arteriosus ◽  
Pulmonary Arteries ◽  
Heat Shock Protein 90 ◽  
Persistent Pulmonary Hypertension ◽  
Resistance Arteries ◽  
Pulmonary Vasodilation ◽  
No Release ◽  
Endothelial Nitric Oxide

Persistent pulmonary hypertension of newborn (PPHN) is associated with decreased nitric oxide (NO) release and impaired pulmonary vasodilation. We investigated the hypothesis that decreased association of heat shock protein 90 (HSP90) with endothelial NO synthase (eNOS) impairs NO release and vasodilation in PPHN. The responses to the NOS agonist ATP were investigated in fetal lambs with PPHN induced by prenatal ligation of ductus arteriosus, and in sham ligation controls. ATP caused dose-dependent vasodilation in control pulmonary resistance arteries, and this response was attenuated in PPHN vessels. The response of control pulmonary arteries to ATP was attenuated by NG-nitro-l-arginine methyl ester (l-NAME), a NOS antagonist, and geldanamycin, an inhibitor of HSP90-eNOS interaction. The attenuated response to ATP observed in PPHN was improved by pretreatment of vessels with l-NAME or 4,5-dihydroxy-1,3-benzene-disulfonate, a superoxide scavenger. Pulmonary arteries from PPHN lambs had decreased basal levels of HSP90 in association with eNOS. Association of HSP90 with eNOS and NO release increased in response to ATP in control pulmonary artery endothelial cells, but not in cells from PPHN lambs. Decreased HSP90-eNOS interactions may contribute to the impaired NO release and vasodilation observed in the ductal ligation model of PPHN.

Diabetes induces pulmonary artery endothelial dysfunction by NADPH oxidase induction

2008 ◽  
Vol 295 (5) ◽  
pp. L727-L732 ◽  
Author(s):  
Jose G. Lopez-Lopez ◽  
Javier Moral-Sanz ◽  
Giovanna Frazziano ◽  
Maria J. Gomez-Villalobos ◽  
Jorge Flores-Hernandez ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Nadph Oxidase ◽  
Pulmonary Arteries ◽  
Diabetic Rats ◽  
Oxidase Inhibitor ◽  
No Synthase ◽  
Superoxide Production ◽  
Regulatory Subunit ◽  
Sprague Dawley ◽  
Relaxant Response

Recent data suggest that diabetes is a risk factor for pulmonary hypertension. The aim of the present study was to analyze whether diabetes induces endothelial dysfunction in pulmonary arteries and the mechanisms involved. Male Sprague-Dawley rats were randomly divided into a control (saline) and a diabetic group (70 mg/kg−1 streptozotocin). After 6 wk, intrapulmonary arteries were mounted for isometric tension recording, and endothelial function was tested by the relaxant response to acetylcholine. Protein expression and localization were measured by Western blot and immunohistochemistry and superoxide production by dihydroethidium staining. Pulmonary arteries from diabetic rats showed impaired relaxant response to acetylcholine and reduced vasoconstrictor response to the nitric oxide (NO) synthase inhibitor l-NAME, whereas the response to nitroprusside and the expression of endothelial NO synthase remained unchanged. Endothelial dysfunction was reversed by addition of superoxide dismutase or the NADPH oxidase inhibitor apocynin. An increase in superoxide production and increased expression of the NADPH oxidase regulatory subunit p47phox were also found in pulmonary arteries from diabetic rats. In conclusion, the pulmonary circulation is a target for diabetes-induced endothelial dysfunction via enhanced NADPH oxidase-derived superoxide production.

Oxidant stress from uncoupled nitric oxide synthase impairs vasodilation in fetal lambs with persistent pulmonary hypertension

2007 ◽  
Vol 292 (4) ◽  
pp. H1812-H1820 ◽  
Author(s):  
Girija G. Konduri ◽  
Ivane Bakhutashvili ◽  
Annie Eis ◽  
Kirkwood Pritchard
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Nitric Oxide Synthase ◽  
Pulmonary Artery ◽  
Ductus Arteriosus ◽  
Oxidant Stress ◽  
Pulmonary Arteries ◽  
Persistent Pulmonary Hypertension ◽  
Pulmonary Vasodilation ◽  
Oxide Synthase

Persistent pulmonary hypertension of newborn (PPHN) is associated with decreased NO release and impaired pulmonary vasodilation. We investigated the hypothesis that increased superoxide (O2•−) release by an uncoupled endothelial nitric oxide synthase (eNOS) contributes to impaired pulmonary vasodilation in PPHN. We investigated the response of isolated pulmonary arteries to the NOS agonist ATP and the NO donor S-nitroso- N-acetylpenicillamine (SNAP) in fetal lambs with PPHN induced by prenatal ligation of ductus arteriosus and in sham-ligated controls in the presence or absence of the NOS antagonist nitro-l-arginine methyl ester (l-NAME) or the O2•− scavenger 4,5-dihydroxy-1,3-benzenedisulfonate (Tiron). ATP caused dose-dependent relaxation of pulmonary artery rings in control lambs but induced constriction of the rings in PPHN lambs. l-NAME, the NO precursor l-arginine, and Tiron restored the relaxation response of pulmonary artery rings to ATP in PPHN. Relaxation to NO was attenuated in arteries from PPHN lambs, and the response was improved by l-NAME and by Tiron. We also investigated the alteration in heat shock protein (HSP)90-eNOS interactions and release of NO and O2•− in response to ATP in the pulmonary artery endothelial cells (PAEC) from these lambs. Cultured PAEC and endothelium of freshly isolated pulmonary arteries from PPHN lambs released O2•− in response to ATP, and this was attenuated by the NOS antagonist l-NAME and superoxide dismutase (SOD). ATP stimulated HSP90-eNOS interactions in PAEC from control but not PPHN lambs. HSP90 immunoprecipitated from PPHN pulmonary arteries had increased nitrotyrosine signal. Oxidant stress from uncoupled eNOS contributes to impaired pulmonary vasodilation in PPHN induced by ductal ligation in fetal lambs.

scholarly journals Superoxide dismutase restores eNOS expression and function in resistance pulmonary arteries from neonatal lambs with persistent pulmonary hypertension

2008 ◽  
Vol 295 (6) ◽  
pp. L979-L987 ◽  
Author(s):  
Kathryn N. Farrow ◽  
Satyan Lakshminrusimha ◽  
William J. Reda ◽  
Stephen Wedgwood ◽  
Lyubov Czech ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Arteries ◽  
Newborn Infants ◽  
Persistent Pulmonary Hypertension ◽  
Ros Production ◽  
Enos Expression ◽  
Neonatal Lambs ◽  
And Function ◽  
Endothelial Nitric Oxide ◽  
The Impact

Endothelial nitric oxide (NO) synthase (eNOS) expression and activity are decreased in fetal lambs with persistent pulmonary hypertension (PPHN). We sought to determine the impact of mechanical ventilation with O2 with or without inhaled NO (iNO) or recombinant human SOD (rhSOD) on eNOS in the ductal ligation model of PPHN. PPHN lambs and age-matched controls were ventilated with 100% O2 for 24 h alone or combined with 20 ppm iNO continuously or a single dose of rhSOD (5 mg/kg) given intratracheally at delivery. In 1-day spontaneously breathing lambs, eNOS expression in resistance pulmonary arteries increased relative to fetal levels. eNOS expression increased in control lambs ventilated with 100% O2, but not in PPHN lambs. Addition of iNO or rhSOD increased eNOS expression and decreased generation of reactive oxygen species (ROS) in PPHN lambs relative to those ventilated with 100% O2 alone. However, only rhSOD restored eNOS function, increased tetrahydrobiopterin (BH4), a critical cofactor for eNOS function, and restored GTP cyclohydrolase I expression in isolated vessels and lungs from PPHN lambs. These data suggest that ventilation of PPHN lambs with 100% O2 increases ROS production, blunts postnatal increases in eNOS expression, and decreases available BH4 in PPHN lambs. Although the addition of iNO or rhSOD diminished ROS production and increased eNOS expression, only rhSOD improved eNOS function and levels of available BH4. Thus therapies designed to decrease oxidative stress and restore eNOS coupling, such as rhSOD, may prove useful in the treatment of PPHN in newborn infants.

scholarly journals Use of sildenafil in an infant with persistent pulmonary hypertension secondary to lung and renal hypoplasia – a case report

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Karen Lavie-Nevo ◽  
Kevin C. Harris ◽  
Joseph Y. Ting
Keyword(s):  
Pulmonary Hypertension ◽  
Case Report ◽  
Right Ventricular ◽  
Ventricular Dysfunction ◽  
Ductus Arteriosus ◽  
Hypertensive Crisis ◽  
Pulmonary Arteries ◽  
Right Ventricular Dysfunction ◽  
Persistent Pulmonary Hypertension ◽  
Renal Hypoplasia

Abstract Background Premature preterm rupture of membranes (PPROM) is reported to be associated with high rates of neonatal mortality and morbidity. Sildenafil has been used in infants with persistent pulmonary hypertension of newborn (PPHN) due to congenital diaphragmatic hernia (CDH) and bronchopulmonary dysplasia (BPD). Recently, Sildenafil has been evaluated as an alternative or adjunctive pulmonary vasodilator. This case report illustrates the use of early sildenafil for PPHN and right ventricular dysfunction in an unusual setting of lung and renal hypoplasia. Case presentation A male infant was born at 37 weeks with a birth weight of 2840 g. Rupture of membranes developed at approximately 24 weeks of gestational age (GA). Bilateral small kidneys (< 2 standard deviations below average) were detected on ultrasound (US) examination at 30 weeks of gestation. The baby developed pneumothorax and pulmonary hypertensive crisis towards the end of the first day. An echocardiogram showed a dilated right ventricle, moderate right ventricular systolic dysfunction, hypoplastic pulmonary arteries and a large patent ductus arteriosus with bidirectional flow. The patient was sedated, paralyzed, and inhaled nitric oxide was administered to decrease the pulmonary resistance. In anticipation of persistent pulmonary hypertension due to the hypoplastic lungs and small calibre of pulmonary arteries, sildenafil was started on day of life (DOL) 5 at a dosage of 0.25 mg/kg/dose Q8H and gradually increased to 2 mg/kg/dose Q8H on DOL 9. The patient was finally extubated on DOL 7 and weaned off of non-invasive respiratory support on DOL 26. Sildenafil was gradually weaned beginning on DOL 21 and discontinued on DOL 48. Repeat echocardiogram assessment at 3 months showed complete resolution of PHT and right ventricular dilatation. Conclusions We describe the early use of sildenafil in treating pulmonary hypertension associated with lung and renal hypoplasia in a non-CDH patient. Following this treatment the patient made a full recovery from right ventricular dysfunction.

Newborn rat response to single vs. combined cGMP-dependent pulmonary vasodilators

2014 ◽  
Vol 306 (2) ◽  
pp. L207-L215 ◽  
Author(s):  
Masahiro Enomoto ◽  
Amish Jain ◽  
Jingyi Pan ◽  
Yulia Shifrin ◽  
Todd Van Vliet ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Synergistic Effect ◽  
Soluble Guanylate Cyclase ◽  
Pulmonary Arteries ◽  
Small Heat Shock Protein ◽  
No Donor ◽  
Clinical Exposure ◽  
Pulmonary Vasodilators ◽  
Pulmonary Vasodilator

Inhaled nitric oxide (NO) and other cGMP- or cAMP-dependent pulmonary vasodilators are often used in combination for the treatment of the persistent pulmonary hypertension of the newborn syndrome. There is in vitro evidence to indicate that NO downregulate the pulmonary vascular response to cGMP-dependent agonists raising concern as to whether a synergistic effect is observed when employing a combined strategy in newborns. Hypothesizing that a synergistic effect is absent, we evaluated newborn and juvenile rat pulmonary arteries to determine the individual and combined vasodilatory effect of cGMP- and cAMP-dependent agonists. In precontracted near-resistance pulmonary arteries, the addition of sildenafil reduced vasorelaxation response to NO donor S-nitroso- N-acetyl penicillamine (SNAP). A similar decrease in SNAP-induced vasodilation was observed in arteries pretreated with BAY 41–2272 (10−9 M), a soluble guanylate cyclase stimulator cGMP, and its downstream protein kinase activator. cGMP also reduced the vasorelaxant response to the cAMP-dependent forskolin. Inhibition of endogenous vascular NO generation enhanced SNAP-induced relaxation. The present data suggest that the mechanism involved in the cGMP desensitization to other relaxant agonists involves downregulation of the small heat shock protein HSP20 and is evident in rat pulmonary and systemic vascular smooth muscle cells. In newborn rats with chronic hypoxia-induced pulmonary hypertension, the combination of sildenafil and inhaled NO resulted in a lesser reduction in pulmonary vascular resistance compared with their individual effect. These data suggest that clinical exposure to one cGMP-dependent pulmonary vasodilator may affect the response to other cGMP- or cAMP-mediated agonists.

Sign in / Sign up

Export Citation Format

Share Document