Maternal melatonin administration mitigates coronary stiffness and endothelial dysfunction, and improves heart resilience to insult in growth restricted lambs

• Published in: The Journal of physiology 2014-06, Vol.592 (12), p.2695-2709
• Main Authors: Tare, Marianne, Parkington, Helena C., Wallace, Euan M., Sutherland, Amy E., Lim, Rebecca, Yawno, Tamara, Coleman, Harold A., Jenkin, Graham, Miller, Suzanne L.
• Format: Article
• Language: English
• Subjects: Animals; Cardiotonic Agents - pharmacology; Cardiotonic Agents - therapeutic use; Coronary Circulation - drug effects; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiopathology; Female; Fetal Growth Retardation - drug therapy; Fetal Growth Retardation - physiopathology; Fetal Heart - drug effects; Fetal Heart - physiopathology; Integrative; Maternal-Fetal Exchange; Melatonin - pharmacology; Melatonin - therapeutic use; Myocardial Contraction - drug effects; Myocardial Reperfusion Injury - drug therapy; Myocardial Reperfusion Injury - physiopathology; Pregnancy; Sheep; Vascular Stiffness - drug effects
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2014.270934

Key points Failure of the placenta to develop and perform gives rise to intrauterine growth restriction (IUGR) in the fetus. IUGR is associated with impaired heart function in childhood and can even persist long term. Oxidative stress is increased in IUGR and we asked if an antioxidant could reduce this. Melatonin is a well‐known and well‐studied hormone, present in all of us, and it has potent antioxidant properties. In this study we administered melatonin to pregnant ewes carrying twins, one with IUGR. Maternal melatonin improved oxygen delivery to the IUGR fetus and strengthened and protected its heart against infarct. After birth, the poor function and stiffness in the coronary arteries of IUGR lambs were entirely prevented by melatonin. Our results demonstrate that administration of melatonin to a mother carrying an IUGR fetus can markedly dampen the adverse heart and artery effects in the offspring following birth. Intrauterine growth restriction (IUGR) is associated with impaired cardiac function in childhood and is linked to short‐ and long‐term morbidities. Placental dysfunction underlies most IUGR, and causes fetal oxidative stress which may impact on cardiac development. Accordingly, we investigated whether antenatal melatonin treatment, which possesses antioxidant properties, may afford cardiovascular protection in these vulnerable fetuses. IUGR was induced in sheep fetuses using single umbilical artery ligation on day 105–110 of pregnancy (term 147). Study 1: melatonin (2 mg h−1) was administered i.v. to ewes on days 5 and 6 after surgery. On day 7 fetal heart function was assessed using a Langendorff apparatus. Study 2: a lower dose of melatonin (0.25 mg h−1) was administered continuously following IUGR induction and the ewes gave birth normally at term. Lambs were killed when 24 h old and coronary vessels studied. Melatonin significantly improved fetal oxygenation in vivo. Contractile function in the right ventricle and coronary flow were enhanced by melatonin. Ischaemia–reperfusion‐induced infarct area was 3‐fold greater in IUGR hearts than in controls and this increase was prevented by melatonin. In isolated neonatal coronary arteries, endothelium‐dependent nitric oxide (NO) bioavailability was reduced in IUGR, and was rescued by modest melatonin treatment. Melatonin exposure also induced the emergence of an indomethacin‐sensitive vasodilation. IUGR caused marked stiffening of the coronary artery and this was prevented by melatonin. Matern