Prenatal hypoxia programs changes in β-adrenergic signaling and postnatal cardiac contractile dysfunction

Prenatal hypoxia leads to an increased risk of adult cardiovascular disease. We have previously demonstrated a programming effect of prenatal hypoxia on the cardiac beta-adrenergic (beta AR) response. The aim of this study was to determine 1) whether the decrease in beta AR sensitivity in prenatally hypoxic 5-wk old chicken hearts is linked to changes in beta(1)AR/beta(2)ARs, G(alpha i) expression and cAMP accumulation and 2) whether prenatal hypoxia has an effect on heart function in vivo. We incubated eggs in normoxia (N, 21% O-2) or hypoxia from day 0 (H, 14% O-2) and raised the posthatchlings to 5 wk of age. Cardiac beta(1)AR/beta(2)ARs were assessed through competitive binding of [H-3]CGP-12177 with specific beta(1)AR or beta(2)AR blockers. G(alpha s) and G(alpha i) proteins were assessed by Western blot and cAMP accumulation by ELISA. Echocardiograms were recorded in anesthetized birds to evaluate diastolic/systolic diameter and heart rate and tissue sections were stained for collagen. We found an increase in relative heart mass, beta(1)ARs, and G(alpha s) in prenatally hypoxic hearts. cAMP levels after isoproterenol stimulation and collagen content was not changed in H compared with N, but in vivo echocardiograms showed systolic contractile dysfunction. The changes in beta AR and G protein subtypes may be indicative of an early compensatory stage in the progression of cardiac dysfunction, further supported by the cardiac hypertrophy and systolic contractile dysfunction. We suggest that it is not the changes in the proximal part of the beta AR system that causes the decreased cardiac contractility, but Ca2+ handling mechanisms further downstream in the beta AR signaling cascade.