Maternal melatonin administration mitigates coronary stiffness and endothelial dysfunction, and improves heart resilience to insult in growth restricted lambs.
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. Maternal melatonin treatment reduces fetal hypoxaemia, improves heart function and coronary blood flow and rescues cardio-coronary deficit induced by IUGR.
Department of Physiology, Monash University, Clayton, Victoria, Australia.
Marianne
M
Tare
Department of Physiology, Monash University, Clayton, Victoria, Australia helena.parkington@monash.edu.
Helena C
HC
Parkington
Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia The Ritchie Centre, MIMR-PHI Institute of Medical Research, Clayton, Victoria, Australia.
Euan M
EM
Wallace
The Ritchie Centre, MIMR-PHI Institute of Medical Research, Clayton, Victoria, Australia.
Amy E
AE
Sutherland
Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia The Ritchie Centre, MIMR-PHI Institute of Medical Research, Clayton, Victoria, Australia.
Rebecca
R
Lim
The Ritchie Centre, MIMR-PHI Institute of Medical Research, Clayton, Victoria, Australia.
Tamara
T
Yawno
Department of Physiology, Monash University, Clayton, Victoria, Australia.
Harold A
HA
Coleman
Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia The Ritchie Centre, MIMR-PHI Institute of Medical Research, Clayton, Victoria, Australia.
Graham
G
Jenkin
Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia The Ritchie Centre, MIMR-PHI Institute of Medical Research, Clayton, Victoria, Australia.
Suzanne L
SL
Miller
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003326:Coronary Circulation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D005260:Female; D005317:Fetal Growth Retardation / Q000188:drug therapy* / Q000503:physiopathology; D005318:Fetal Heart / Q000187:drug effects* / Q000503:physiopathology; D008431:Maternal-Fetal Exchange; D008550:Melatonin / Q000494:pharmacology / Q000627:therapeutic use*; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000503:physiopathology; D011247:Pregnancy; D012756:Sheep; D059289:Vascular Stiffness / Q000187:drug effects
D002316:Cardiotonic Agents; D008550:Melatonin