Chronic hypoxia during gestation leads to an increased risk to develop Neonatal Pulmonary Hypertension (NPH)1. Newborns with NPH show a vascular dysfunction due to augmented oxidative stress and vascular remodelling2. Nowadays, the only approved treatment is oxygen supplementation and inhaled nitric oxide, however, it only works in 30% - 50% of the patients3. Our laboratory proposes a combined antioxidant and anti-remodelling treatment with melatonin and hemin to improve vascular function in NPH.
Materials and methods:
15 lambs were gestated, born and studied at 3600 m. We developed 3 experimental groups: a) Control (CN, vehicle treatment, n=5), b) Melatonin (M, melatonin 1 mg*kg-1, n=5), and c) Melatonin-Hemin (MH, melatonin, 1mg*kg-1; hemin, 10 mg*kg-1 n=5), all groups treated for 21 days. After 7 days of treatment termination, animals were euthanized. We assessed vascular function by wire miography and pulmonary artery tissue was collected for molecular biology assessment. All procedures were approved by the Local Bioethics Committee (CBA #0761 FMUCH).
Relaxation in response to methacholine an SNP was improved in pulmonary resistance arteries of animals treated with the combined therapy. mRNA COX2 expression was increased in MH group without differences in protein levels. Prostacyclin synthase and its receptor IP levels were elevated in MH animals. Further, MH induced an increase in protein levels of sGC-PKG pathway in lung tissue. There was an increase in hemoxygenase-2 and BKCa protein levels in MH group compared to control group.
Conclusion: Combined treatment improve vasodilator function. Further, molecular markers of endothelium-dependent and independent vasodilator function were enhanced in lung tissue. These effects were greater than the individual drug treatments.
Funding: FONDECYT 1151119
1. Herrera et al. Am J Physiol. 299:R1676-R1684, 2007.
2. Jain et al. Semin Fetal Neonatal Med. 20(4):262-71, 2015.
3. Lakshminrushimha et al. Semin Perinatol. 40:160-73, 2016.