Proceedings of The Physiological Society

Physiology 2016 (Dublin, Ireland) (2016) Proc Physiol Soc 37, PCA031

Poster Communications

Direct effects of pravastatin or melatonin on cardiovascular function in the chronically-hypoxic fetus: A comparison of two antioxidant strategies

N. Itani1, K. L. Skeffington1, Y. Niu1, C. Beck1, D. A. Giussani1

1. Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.

Maternal treatment with either pravastatin or melatonin to protect growth in the hypoxic fetus in complicated pregnancy is currently undergoing multicentre human clinical trials (Constantine et al. (2013). Obstet Gynecol. 121: 349; Alers et al. (2013). BMJ Open 3(12):e004141). However, whether these treatments have additional beneficial or detrimental effects on the hypoxic fetus is completely unknown. The chick embryo is the only established animal model to isolate the direct effects of any therapy on the fetus independent of effects on the maternal or placental physiology. Therefore, this study investigated the effects on cardiac and vascular function of treatment with either pravastatin or melatonin in the hypoxic chick embryo. Fertilised eggs (n=7-10 per group) were incubated under normoxia (N) or hypoxia (H, 14%) from day 1 (term: 21 days). Pravastatin (1, Melatonin (1 or vehicle was injected daily into the air cell from day 13 of incubation, which equates to 25 weeks of human pregnancy. At day 19, the embryo was euthanized and cardiovascular function was determined using a Langendorff preparation and a wire myograph. Chronic fetal hypoxia impaired systolic (reduced left ventricular developed pressure, LVDP) and diastolic (elevated LV end diastolic pressure, LVEDP) function (Fig.1). While treatment with melatonin rescued systolic function, pravastatin rescued diastolic function in hypoxic embryos. Chronic hypoxia induced endothelial dysfunction in femoral vessels (N: 7.0±0.1 and H: 6.3±0.1, sensitivity [pD2] to log [acetylcholine], P<0.05). Treatment with melatonin or pravastatin rescued endothelial function in hypoxic embryos (HM: 7.0±0.1, HP: 7.0±0.2). We show that human clinically-relevant doses of antioxidants being trialled clinically at present to protect the fetus in high risk pregnancy also have direct beneficial effects on the developing cardiovascular system of the hypoxic fetus.

Where applicable, experiments conform with Society ethical requirements