SOD and inhaled nitric oxide normalize phosphodiesterase 5 expression and activity in neonatal lambs with persistent pulmonary hypertension

Phosphodiesterase 5 (PDE5) and soluble guanylate cyclase (sGC) are key regulators of cGMP and pulmonary vascular tone. We sought to determine the impact of mechanical ventilation with O2 with or without inhaled nitric oxide (iNO) or recombinant human Cu/Zn SOD (rhSOD) on sGC, PDE5, and cGMP in the ovine ductal ligation model of persistent pulmonary hypertension of the newborn (PPHN). PPHN lambs were ventilated with 100% O2 for 24 h alone or combined with either inhalation of 20 parts per million (ppm) iNO continuously or a single intratracheal dose of rhSOD (5 mg/kg). Ventilated PPHN lambs were compared with PPHN fetuses, control fetuses, and 1-day-old spontaneously breathing lambs (1DSB). In the small pulmonary arteries of 1DSB lambs, sGC expression increased, PDE5 expression decreased, and cGMP concentrations increased relative to fetal levels. In PPHN lambs ventilated with 100% O2, sGC activity increased to levels comparable with 1DSB levels. However, PDE5 expression and activity increased, and cGMP levels remained at fetal levels. Addition of either iNO or rhSOD decreased PDE5 expression and activity in PPHN lambs and increased cGMP levels to levels comparable with 1DSB lambs. These data suggest that ventilation of PPHN lambs with 100% O2 impairs cGMP-mediated vasodilation in part due to increased PDE5 expression and activity. The addition of either iNO or rhSOD normalized PDE5 and cGMP levels. Thus therapies designed to decrease PDE5 and increase cGMP, such as iNO and rhSOD, may prove useful in the treatment of PPHN in newborn infants.

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Factors Affecting the Response to Inhaled Nitric Oxide Therapy in Persistent Pulmonary Hypertension of the Newborn Infants

Yonsei Medical Journal ◽

10.3349/ymj.2004.45.1.49 ◽

2004 ◽

Vol 45 (1) ◽

pp. 49 ◽

Cited By ~ 12

Author(s):

Soo Jung Hwang ◽

Kye Hyang Lee ◽

Jong Hee Hwang ◽

Chang Won Choi ◽

Jae Won Shim ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Newborn Infants ◽

Inhaled Nitric Oxide ◽

Persistent Pulmonary Hypertension ◽

Factors Affecting ◽

Nitric Oxide Therapy

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

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.90238.2008 ◽

2008 ◽

Vol 295 (6) ◽

pp. L979-L987 ◽

Cited By ~ 104

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.

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Longitudinal follow-up of a cohort of newborn infants treated with inhaled nitric oxide for persistent pulmonary hypertension

The Journal of Pediatrics ◽

10.1016/s0022-3476(97)70126-4 ◽

1997 ◽

Vol 131 (1) ◽

pp. 70-75 ◽

Cited By ~ 49

Author(s):

Adam A. Rosenberg ◽

Jan M. Kennaugh ◽

Susan G. Moreland ◽

Lucy M. Fashaw ◽

Kathy A. Hale ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Newborn Infants ◽

Inhaled Nitric Oxide ◽

Persistent Pulmonary Hypertension

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Effect of inhaled nitric oxide on endothelin-1 and cyclic guanosine 5`-monophosphate plasma concentrations in newborn infants with persistent pulmonary hypertension

The Journal of Pediatrics ◽

10.1016/s0022-3476(97)70245-2 ◽

1997 ◽

Vol 130 (4) ◽

pp. 603-611 ◽

Cited By ~ 59

Author(s):

Helen Christou ◽

Ian Adatia ◽

Linda J. Van Marter ◽

Janie W. Kane ◽

John E. Thompson ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Plasma Concentrations ◽

Newborn Infants ◽

Inhaled Nitric Oxide ◽

Persistent Pulmonary Hypertension ◽

Endothelin 1

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The Impact of Combined Oral Sildenafil and Inhaled Nitric Oxide for Treating Persistent Pulmonary Hypertension of the Newborn: A Single Center Experience

Gynecology Obstetrics and Reproductive Medicine ◽

10.21613/gorm.2016.656 ◽

2017 ◽

Vol 23 (2) ◽

pp. 100

Author(s):

Hayriye Gozde Kanmaz ◽

Mehmet Büyüktiryaki ◽

Şerife Suna Oğuz ◽

Evrim Dizdar Alyamac ◽

Fatma Nur Sarı ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Therapy Group ◽

Combined Therapy ◽

Newborn Infants ◽

Inhaled Nitric Oxide ◽

Single Center Experience ◽

Group I ◽

Nitric Oxide Therapy ◽

The Impact

Objective: We aimed to compare the effect of the combined therapy, sildenafil and inhaled nitric oxide with inhaled nitric oxide monotherapy for the treatment of Pulmonary Hypertension of the Newborn.Study Design: Newborn infants (gestational age greater than 34 weeks) who were diagnosed with pulmonary hypertension between December 2008 and 2010 were retrospectively evaluated. Group I (n=14) received monotherapy with inhaled nitric oxide and Group II (n=9) received combined therapy with inhaled nitric oxide and oral sildenafil. Primary outcome was to compare the duration of inhaled nitric oxide therapy between groups.Results: Demographic characteristics were similar between the groups. Combination therapy was associated with early weaning of inhaled nitric oxide (4.8±1.5 vs. 13.5±7.6 hours). The duration of inhaled nitric oxide therapy was slightly shorter in combined therapy group (75[24-125] vs. 109[24-210] hours), however, the difference was insignificant (p=0.2). The incidence of mortality and neonatal outcomes were similar between the groups (p>0.05).Conclusion: Combined therapy did not result in shorter duration of inhaled nitric oxide therapy. Further well designed and larger studies that will elucidate the benefits of combination therapies and optimal therapy whereinhaled nitric oxide is not available are warranted.

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Time limits for a failed response to inhaled nitric oxide in newborn infants with persistent pulmonary hypertension: A retrospective observational study

Journal of Neonatal-Perinatal Medicine ◽

10.3233/npm-2010-0106 ◽

2010 ◽

Vol 3 (2) ◽

pp. 141-146

Author(s):

Husam Salama ◽

Wissam Adlburaki ◽

Amani Saeed Ibrahim ◽

Samawal Lutfi ◽

Nawal Magzoob

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Observational Study ◽

Newborn Infants ◽

Inhaled Nitric Oxide ◽

Persistent Pulmonary Hypertension ◽

Retrospective Observational Study ◽

Time Limits

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Inhaled Nitric Oxide at Birth Reduces Pulmonary Vascular Resistance and Improves Oxygenation in Preterm Lambs

Children ◽

10.3390/children8050378 ◽

2021 ◽

Vol 8 (5) ◽

pp. 378

Author(s):

Satyan Lakshminrusimha ◽

Sylvia F. Gugino ◽

Krishnamurthy Sekar ◽

Stephen Wedgwood ◽

Carmon Koenigsknecht ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Pulmonary Vascular Resistance ◽

Preterm Infants ◽

Vascular Resistance ◽

Inhaled Nitric Oxide ◽

Persistent Pulmonary Hypertension ◽

Inhaled No ◽

Birth Preterm

Resuscitation with 21% O2 may not achieve target oxygenation in preterm infants and in neonates with persistent pulmonary hypertension of the newborn (PPHN). Inhaled nitric oxide (iNO) at birth can reduce pulmonary vascular resistance (PVR) and improve PaO2. We studied the effect of iNO on oxygenation and changes in PVR in preterm lambs with and without PPHN during resuscitation and stabilization at birth. Preterm lambs with and without PPHN (induced by antenatal ductal ligation) were delivered at 134 d gestation (term is 147–150 d). Lambs without PPHN were ventilated with 21% O2, titrated O2 to maintain target oxygenation or 21% O2 + iNO (20 ppm) at birth for 30 min. Preterm lambs with PPHN were ventilated with 50% O2, titrated O2 or 50% O2 + iNO. Resuscitation with 21% O2 in preterm lambs and 50%O2 in PPHN lambs did not achieve target oxygenation. Inhaled NO significantly decreased PVR in all lambs and increased PaO2 in preterm lambs ventilated with 21% O2 similar to that achieved by titrated O2 (41 ± 9% at 30 min). Inhaled NO increased PaO2 to 45 ± 13, 45 ± 20 and 76 ± 11 mmHg with 50% O2, titrated O2 up to 100% and 50% O2 + iNO, respectively, in PPHN lambs. We concluded that iNO at birth reduces PVR and FiO2 required to achieve target PaO2.

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