Maternal Allopurinol Prevents Cardiac Dysfunction in Adult Male Offspring Programmed by Chronic Hypoxia During Pregnancy.

Abstract

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 ischaemia-reperfusion (IR) in a Langendorff preparation. Sympathetic dominance, perfusate creatine kinase (CK) and lactate dehydrogenase (LDH) and the cardiac protein expression of the 1 adrenergic receptor, the muscarinic type-2 acetylcholine receptor and the sarcoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) 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 IR (left ventricular diastolic pressure, LVDP, AUC recovery -19.1 %; all P<0.05). Increased sympathetic reactivity (heart rate, +755.5 %, LVDP, +418.9 %) contributed to the enhanced myocardial contractility (P<0.05). Perfusate CK (+431 %) and LDH (+251.3 %) and the cardiac expression of SERCA2a (+71.4 %) were also elevated (P<0.05), further linking molecular markers of cardiac stress and injury to dysfunction. Maternal Allopurinol restored all functional and molecular indices of cardiac pathology. The data support a link between xanthine oxidase-derived oxidative stress in hypoxic pregnancy and cardiac dysfunction in the adult offspring, providing a target for early intervention in the developmental programming of heart disease.