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DEVELOPMENTAL PHYSIOLOGY AND PREGNANCY

Maternal low-protein diet programs cardiac -adrenergic response and signaling in 3-mo-old male offspring

Department of Clinical Biochemistry, University of Cambridge, Addenbrookes Hospital, Cambridge, United Kingdom

Submitted 23 August 2005 ; accepted in final form 13 February 2006

Low birth weight in humans is associated with an increased risk of cardiovascular disease. Humans with heart failure have a reduced -adrenergic response. The aim of this study was to investigate the hemodynamic response to the -adrenergic agonist isoproterenol and to identify molecular deficiencies that may be predictive of cardiac failure in a low-birth weight rodent model that develops insulin resistance and type 2 diabetes in adulthood. Wistar rats were fed a control or a low-protein (LP) diet throughout pregnancy and lactation. The resting heart rate and blood pressure of the 3-mo-old male offspring of these dams, termed "control" and "LP" groups, respectively, and their responses to isoproterenol (ISO) infusion were monitored by radiotelemetry. The protein expression of -adrenergic signaling components was also measured by Western blot analysis. Basal heart rate was increased in LP offspring (P < 0.04), although mean arterial pressure was comparable with controls. Chronotropic effects of ISO were blunted in LP offspring with significant delays to maximal response (P = 0.01), a shorter duration of response (P = 0.03), and a delayed return to baseline (P = 0.01) at the lower dose (0.1 µg·kg^–1·min^–1). At the higher dose (1.0 µg·kg^–1·min^–1 ISO), inotropic response was blunted (P = 0.03) but quicker (P = 0.001). In heart tissue of LP offspring, ₁-adrenergic receptor expression was reduced (P < 0.03). ₁-Adrenergic receptor kinase and both stimulatory and inhibitory G protein levels remained unchanged, whereas -arrestin levels were higher (P < 0.03). Finally, insulin receptor- expression was reduced in LP offspring (P < 0.012). LP offspring have reduced -adrenergic responsiveness and attenuated adrenergic and insulin signaling, suggesting that intrauterine undernutrition alters heart failure risk.

-adrenergic receptor; insulin receptor; -arrestin

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