Melatonin reduces oxidative stress and improves vascular function in pulmonary hypertensive newborn sheep.
Pulmonary hypertension of the newborn (PHN) constitutes a critical condition with severe cardiovascular and neurological consequences. One of its main causes is hypoxia during gestation, and thus, it is a public health concern in populations living above 2500 m. Although some mechanisms are recognized, the pathophysiological facts that lead to PHN are not fully understood, which explains the lack of an effective treatment. Oxidative stress is one of the proposed mechanisms inducing pulmonary vascular dysfunction and PHN. Therefore, we assessed whether melatonin, a potent antioxidant, improves pulmonary vascular function. Twelve newborn sheep were gestated, born, and raised at 3600 meters. At 3 days old, lambs were catheterized and daily cardiovascular measurements were recorded. Lambs were divided into two groups, one received daily vehicle as control and another received daily melatonin (1 mg/kg/d), for 8 days. At 11 days old, lung tissue and small pulmonary arteries (SPA) were collected. Melatonin decreased pulmonary pressure and resistance for the first 3 days of treatment. Further, melatonin significantly improved the vasodilator function of SPA, enhancing the endothelial- and muscular-dependent pathways. This was associated with an enhanced nitric oxide-dependent and nitric oxide independent vasodilator components and with increased nitric oxide bioavailability in lung tissue. Further, melatonin reduced the pulmonary oxidative stress markers and increased enzymatic and nonenzymatic antioxidant capacity. Finally, these effects were associated with an increase of lumen diameter and a mild decrease in the wall of the pulmonary arteries. These outcomes support the use of melatonin as an adjuvant in the treatment for PHN.
Programa de Fisiopatología, Instituto de Ciencias Biomédicas (ICBM), Facultad de Medicina, Universidad de Chile, Providencia, Santiago, Chile.
Flavio
F
Torres
Alejandro
A
González-Candia
Camilo
C
Montt
Germán
G
Ebensperger
Magdalena
M
Chubretovic
María
M
Serón-Ferré
Roberto V
RV
Reyes
Aníbal J
AJ
Llanos
Emilio A
EA
Herrera
D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D008168:Lung / Q000098:blood supply / Q000187:drug effects*; D008550:Melatonin / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000502:physiology; D012756:Sheep
D000975:Antioxidants; D008550:Melatonin
antioxidant system; chronic hypoxia; nitric oxide; oxidative stress; pulmonary hypoxic vasoconstriction; vascular function