Melatonin Attenuates Pulmonary Hypertension in Chronically Hypoxic Rats

Abstract

Chronic hypoxia induces pulmonary hypertension and vascular remodeling, which are clinically relevant to patients with chronic obstructive pulmonary disease (COPD) associated with a decreased level of nitric oxide (NO). Oxidative stress and inflammation play important roles in the pathophysiological processes in COPD. We examined the hypothesis that daily administration of melatonin (10 mg/kg) mitigates the pulmonary hypertension and vascular remodeling in chronically hypoxic rats. The right ventricular systolic pressure (RVSP) and the thickness of pulmonary arteriolar wall were measured from normoxic control, vehicle- and melatonin-treated hypoxic rats exposed to 10% O2 for 14 days. Levels of markers for oxidative stress (malondialdhyde) and inflammation (tumor necrosis factor-α (TNFα), inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2)) and the expressions of total endothelial NO synthase (eNOS) and phosphorylated eNOS at serine1177 (ser1177) were determined in the lung tissue. We found that the RVSP and the thickness of the arteriolar wall were significantly increased in the vehicle-treated hypoxic animals with elevated levels of malondialdhyde and mRNA expressions of the inflammatory mediators, when compared with the normoxic control. In addition, the phosphorylated eNOS (ser1177) level was significantly decreased, despite an increased eNOS expression in the vehicle-treated hypoxic group. Melatonin treatment significantly attenuated the levels of RVSP, thickness of the arteriolar wall, oxidative and inflammatory markers in the hypoxic animals with a marked increase in the eNOS phosphorylation in the lung. These results suggest that melatonin attenuates pulmonary hypertension by antagonizing the oxidative injury and restoration of NO production.

El tratamiento postnatal con melatonina modula la expresión de agentes prostanoides en pulmón de neonatos de oveja con hipertensión pulmonar

“…Por lo tanto, una disminución de la COX-2 podría ser indicador de menor estrés oxidativo e inflamación pulmonar. Con respecto a lo anterior, se ha demostrado que melatonina disminuye el estrés oxidativo y la presión pulmonar en neonatos 15,16 y adultos 26 de modelos animales. Los efectos antioxidantes de melatonina están asociados a sus características de: 1) scavenger de radicales libres, 2) inducción de la maquinaria enzimática antioxidante y 3) disminución de la expresión de enzimas prooxidantes 27 , lo cual disminuye el tono oxidativo en el territorio pulmonar 15,17,18 .…”

Pleiotropic Effects of Melatonin

“…[41] A recent study reported that melatonin significantly attenuated the levels of RV systolic pressure, thickness of the arteriolar wall, oxidative and inflammatory markers in the hypoxic animals with a marked increase in the endothelial nitric oxide synthase phosphorylation in the lung. [42] Hung et al concluded their finding that that melatonin attenuated pulmonary hypertension by reversing injury caused due to the oxidative stress in lungs and restoring nitric oxide production. [42] Melatonin also have protective effects on cardiac tissues and thereby protects heart, due to antiatherosclerotic activities.…”

“…[42] Hung et al concluded their finding that that melatonin attenuated pulmonary hypertension by reversing injury caused due to the oxidative stress in lungs and restoring nitric oxide production. [42] Melatonin also have protective effects on cardiac tissues and thereby protects heart, due to antiatherosclerotic activities. [43,44] In 2015, Cheng et al, demonstrated that melatonin treatment had significantly reduced the number and areas of atheromatous plaques in an animal model involving rabbit.…”

Fetal programming and its effects on vascular pulmonary circulation

“…Useful results might derive by other approaches. Recently, it has been reported that the administration of antioxidants and anti-remodeling agents associated with the vasodilator therapies could have beneficial effects in new-borns [40][41][42][43][44][45][46] . From this point of view, melatonin (N-acetyl-5-methoxytryptamine, an indoleamine molecule), appears to be an effective agent for PHN, markedly improving pulmonary vascular function.…”

“…However, the date until now obtained derive only from animal studies. Consequently, future studies should be performed for: (1) optimizing doses and/or therapeutic windows to improve the functional and anti-remodeling effects in animal models, as preclinical studies ; and (2) extending these investigations to human pregnant women and new-borns [40][41][42][43][44][45][46] .…”