Antioxidant treatment improves neonatal survival and prevents impaired cardiac function at adulthood following neonatal glucocorticoid therapy.
Glucocorticoids are widely used to treat chronic lung disease in premature infants but their longer-term adverse effects on the cardiovascular system raise concerns. We reported that neonatal dexamethasone treatment in rats induced in the short term molecular indices of cardiac oxidative stress and cardiovascular tissue remodelling at weaning, and that neonatal combined antioxidant and dexamethasone treatment was protective at this time. In this study, we investigated whether such effects of neonatal dexamethasone have adverse consequences for NO bioavailability and cardiovascular function at adulthood, and whether neonatal combined antioxidant and dexamethasone treatment is protective in the adult. Newborn rat pups received daily i.p. injections of a human-relevant tapering dose of dexamethasone (D; n = 8; 0.5, 0.3, 0.1 μg g(-1)) or D with vitamins C and E (DCE; n = 8; 200 and 100 mg kg(-1), respectively) on postnatal days 1-3 (P1-3); vitamins were continued from P4 to P6. Controls received equal volumes of vehicle from P1 to P6 (C; n = 8). A fourth group received vitamins alone (CCE; n = 8). At P100, plasma NO metabolites (NOx) was measured and isolated hearts were assessed under both Working and Langendorff preparations. Relative to controls, neonatal dexamethasone therapy increased mortality by 18% (P < 0.05). Surviving D pups at adulthood had lower plasma NOx concentrations (10.6 ± 0.8 vs. 28.0 ± 1.5 μM), an increased relative left ventricular (LV) mass (70 ± 2 vs. 63 ± 1%), enhanced LV end-diastolic pressure (14 ± 2 vs. 8 ± 1 mmHg) and these hearts failed to adapt output with increased preload (cardiac output: 2.9 ± 2.0 vs. 10.6 ± 1.2 ml min(-1)) or afterload (cardiac output: -5.3 ± 2.0 vs.1.4 ± 1.2 ml min(-1)); all P < 0.05. Combined neonatal dexamethasone with antioxidant vitamins improved postnatal survival, restored plasma NOx and protected against cardiac dysfunction at adulthood. In conclusion, neonatal dexamethasone therapy promotes cardiac dysfunction at adulthood. Combined neonatal treatment with antioxidant vitamins is an effective intervention.
D. A. Giussani: Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK. dag26@cam.ac.uk.
Youguo
Y
Niu
Emilio A
EA
Herrera
Rhys D
RD
Evans
Dino A
DA
Giussani
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000008:administration & dosage / Q000627:therapeutic use*; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000627:therapeutic use*; D002302:Cardiac Output; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D003907:Dexamethasone / Q000009:adverse effects*; D006339:Heart Rate; D008297:Male; D009569:Nitric Oxide / Q000097:blood; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D020257:Ventricular Remodeling; D014810:Vitamin E / Q000008:administration & dosage / Q000627:therapeutic use*; D014815:Vitamins / Q000008:administration & dosage / Q000627:therapeutic use*
D000975:Antioxidants; D014815:Vitamins; D014810:Vitamin E; D009569:Nitric Oxide; D003907:Dexamethasone; D001205:Ascorbic Acid