Melatonin reduces oxidative stress and improves vascular function in pulmonary hypertensive newborn sheep

Abstract

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.

Melatonin Attenuates Pulmonary Hypertension in Chronically Hypoxic Rats

“…Consistent with findings in previous studies [24,26], we found that chronic hypoxia induced a significant elevated level of lipid peroxidation in the lungs, which was mitigated by the melatonin treatment. It has been shown that hypoxia increased the levels of lipid peroxidation in pulmonary endothelial cells and also the plasma glutathione disulfide in the animal [27,28].…”

“…In addition, melatonin could induce endothelium-dependent vasorelaxation with an increase in the NO production mediated by elevated NOS activity [22,23]. Recent studies have shown that melatonin treatment could elevate the NO availability in the lungs of newborn sheep at high altitude [24] and also alleviate the severe pulmonary hypertension induced by monocrotaline [25] or intermittent hypoxia [26] in rats. However, it is unclear whether the melatonin treatment might ameliorate the pulmonary hypertension induced by chronic hypoxia, which is clinical relevance to the pathophysiological cascade in COPD patients.…”

Melatonin for prevention of placental malperfusion and fetal compromise associated with intrauterine inflammation‐induced oxidative stress in a mouse model

“…Other studies also showed that melatonin has emerged as a promising resource for improving neurological recovery from stroke and ischemic brain damage in adults . Torres et al showed that melatonin reduces oxidative stress and improves vascular vasodilator function of small pulmonary arteries in pulmonary hypertensive newborn sheep . The mechanisms by which melatonin prevents placental malperfusion remains uncertain, but research has focused on melatonin's antioxidative and anti‐inflammatory effects and its immune modulation.…”

Pharmacological approaches in either intermittent or permanent hypoxia: A tale of two exposures

“…Novel treatments have been proposed to decrease the oxidative stress and diminish pulmonary hypertension and cardiovascular remodeling. Recently, we have shown that melatonin increases the enzymatic antioxidants mechanisms and improves pulmonary endothelial function associated with a slight increase of the luminal radius of pulmonary arteries [70]. Interestingly, the same treatment also improved vascular function and decreased oxidative stress in the neonatal brain [95].…”

“…The pulmonary hypertension is a condition with an elevated pulmonary vascular PVR, as a result of an initial vasoconstriction followed by a progressive vascular remodeling [67,69,70]. Both, vascular vasoconstriction and vascular remodeling end up in a significant reduction of the lumen of the intrapulmonary arteries increasing the PVR [65,67,71].…”