Melatonin long‐lasting beneficial effects on pulmonary vascular reactivity and redox balance in chronic hypoxic ovine neonates

Abstract

Pulmonary arterial hypertension of the neonate (PAHN) is a pathophysiological condition characterized by maladaptive pulmonary vascular remodeling and abnormal contractile reactivity. This is a multifactorial syndrome with chronic hypoxia and oxidative stress as main etiological drivers, and with limited effectiveness in therapeutic approaches. Melatonin is a neurohormone with antioxidant and vasodilator properties at the pulmonary level. Therefore, this study aims to test whether a postnatal treatment with melatonin during the neonatal period improves in a long-lasting manner the clinical condition of PAHN. Ten newborn lambs gestated and born at 3600 m were used in this study, five received vehicle and five received melatonin in daily doses of 1 mg kg −1 for the first 3 weeks of life. After 1 week of treatment completion, lung tissue and small pulmonary arteries (SPA) were collected for wire myography, molecular biology, and morphostructural analyses. Melatonin decreased pulmonary arterial pressure the first 4 days of treatment. At 1 month old, melatonin decreased the contractile response to the vasoconstrictors K + , TX 2 , and ET-1. Further, melatonin increased the endothelium-dependent and muscle-dependent vasodilation of SPA. Finally, the treatment decreased pulmonary oxidative stress by inducing antioxidant enzymes and diminishing pro-oxidant sources. In conclusion, melatonin improved vascular reactivity and oxidative stress at the pulmonary level in PAHN lambs gestated and born in chronic hypoxia. K E Y W O R D Schronic hypoxia, melatonin treatment, oxidative stress, pulmonary hypertension of the neonate, reactive oxygen species

Comment on Melatonin as a potential adjuvant treatment for COVID-19

“…The effects of melatonin appear to be very fast since our findings describe that at the first day of oral administration (1 mg/kg), melatonin reduced in 5 mmHg the pulmonary arterial pressure in neonatal lambs born under hypoxia, without side effects such as systemic hypotension or sleepiness [2,3]. Additionally, with either 7 or 21 days of treatment, small pulmonary arteries showed improved endothelial function ex vivo with a greater vasodilator capacity [2,3]. The latter was associated with increased nitric oxide -dependent and -independent vasodilator functions.…”

“…The latter was associated with increased nitric oxide -dependent and -independent vasodilator functions. Interestingly, one of the nitric oxide independent affected mechanisms, was the enhanced expression of the prostacyclin vasodilator pathway [3,4]. The aforementioned findings were also associated with increased expression and/or activity of the endogenous antioxidant enzymes, superoxide dismutase and catalase, an enhanced plasma antioxidant capacity and a marked decreased in pulmonary oxidative stress markers [2,3].…”

“…Interestingly, one of the nitric oxide independent affected mechanisms, was the enhanced expression of the prostacyclin vasodilator pathway [3,4]. The aforementioned findings were also associated with increased expression and/or activity of the endogenous antioxidant enzymes, superoxide dismutase and catalase, an enhanced plasma antioxidant capacity and a marked decreased in pulmonary oxidative stress markers [2,3]. Furthermore, these effects were associated with a diminished vascular remodeling of the pulmonary circulation after 1 week of treatment [5].…”

The newborn sheep translational model for pulmonary arterial hypertension of the neonate at high altitude

“…90 In fact, several studies have linked increased ROS with neonatal pulmonary hypertension and have proposed antioxidant treatments. 23,35,[91][92][93][94][95][96][97] For instance, melatonin treatment as an antioxidant, either antenatal [98][99][100][101][102] or postnatal, 23,35,97 has been successfully studied using sheep models (Table 2).…”

“…Some of the most commonly used mammalian models of antenatal and perinatal hypoxia include sheep, 4,[17][18][19][20][21][22][23] rats, 24 mice, 25 piglets, 26 guinea pigs, 5,27,28 and llamas. [29][30][31][32] Sheep have been used as a model for lung development and pulmonary function for several reasons.…”