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Background: Prematurity is strongly associated with poor respiratory function in the neonate. Rescue therapies include treatment with glucocorticoids due to their anti-inflammatory and maturational effects on the developing lung. However, glucocorticoid treatment in the infant can increase the risk of long-term cardiovascular complications including hypertension, cardiac, and endothelial dysfunction. Accumulating evidence implicates a molecular link between glucocorticoid excess and depletion of nitric oxide (NO) bioavailability as a mechanism underlying the detrimental effects of postnatal steroids on the heart and circulation. Therefore, combined glucocorticoid and statin therapy, by increasing NO bioavailability, may protect the developing cardiovascular system while maintaining beneficial effects on the lung. Methods: We investigated combined glucocorticoid and statin therapy using an established rodent model of prematurity and combined experiments of cardiovascular function in vivo, with those in isolated organs as well as measurements at the cellular and molecular levels. Results: We show that neonatal glucocorticoid treatment increases the risk of later cardiovascular dysfunction in the offspring. Underlying mechanisms include decreased circulating NO bioavailability, sympathetic hyper-reactivity, and NO-dependent endothelial dysfunction. Combined neonatal glucocorticoid and statin therapy protects the developing cardiovascular system by normalizing NO and sympathetic signaling, without affecting pulmonary maturational or anti-inflammatory effects of glucocorticoids. Conclusions: Therefore, combined glucocorticoid and statin therapy may be safer than glucocorticoids alone for the treatment of preterm birth.

Integrating functional and molecular levels, we investigated the effects of maternal treatment with a xanthine oxidase inhibitor on the programming of cardiac dysfunction in adult offspring using an established rat model of hypoxic pregnancy. Female Wistar rats were divided into normoxic or hypoxic (13% O2) pregnancy±maternal allopurinol treatment (30 mg kg-1 d-1). At 4 months, hearts were isolated from 1 male per litter per outcome variable to determine cardiac function and responses to ischemia-reperfusion in a Langendorff preparation. Sympathetic dominance, perfusate CK (creatine kinase) and LDH (lactate dehydrogenase) and the cardiac protein expression of the β1-adrenergic receptor, the M2 Ach receptor (muscarinic type-2 acetylcholine receptor), and the SERCA2a (sarcoplasmic reticulum Ca2+ ATPase 2a) were determined. Relative to controls, offspring from hypoxic pregnancy showed elevated left ventricular end diastolic pressure (+34.7%), enhanced contractility (dP/dtmax, +41.6%), reduced coronary flow rate (-21%) and an impaired recovery to ischemia-reperfusion (left ventricular diastolic pressure, area under the curve recovery -19.1%; all P