Early-Life Sodium Restriction Programs Autonomic Dysfunction and Salt- Sensitivity in Male C57BL/6J Mice.

Abstract

Preterm birth increases the risk of cardiometabolic disease in adulthood. Infants born during the second trimester of pregnancy, a critical period of hypothalamic development, are at risk of sodium (Na) depletion due to renal immaturity and large urine Na losses. We previously demonstrated in male mice that Na restriction during the equivalent mouse hypothalamic development period (PD21-PD42) programs long-term changes in energy balance via increased thermogenic sympathetic nervous activity. We therefore hypothesized that early-life Na restriction programs changes in cardiovascular control via altered autonomic activity. C57BL/6J male mice were supplied a low (0.04%) Na or supplemented (0.30%) Na diet from PD21-PD42, before return to standard (0.15%) Na diet. Hemodynamic and autonomic functions were assessed by radiotelemetry and acute administration of autonomic antagonists before and after all animals were switched to a high Na diet (HSD; 1% Na) at 12 weeks of age. Mice were additionally treated with the angiotensin II type 1 receptor (AT₁R) antagonist, losartan, for two weeks. On standard diet, early-life Na restriction resulted in small but significantly different hemodynamic responses to autonomic blockers without effect on systolic blood pressure (SBP) or heart rate (HR). HSD increased SBP in 0.04% but not 0.30% Na mice, accompanied by increased cardiac sympathetic activity. Losartan had a greater BP lowering effect in early life Na-restricted mice. Our findings suggest Na restriction during a critical hypothalamic developmental period programs long-term changes in autonomic control of cardiovascular functions and may offer insight into the increased risk of cardiovascular disease in former preterm infants.