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Early-life sodium restriction programs autonomic dysfunction and salt sensitivity in male C57BL/6J mice
Alisha A Ziegler1, Samuel B R Lawton1, Eva M Fekete1
1Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States.
Insights
Early-life sodium restriction programs long-term changes in cardiovascular autonomic control. This may explain increased heart disease risk in preterm infants due to altered sodium homeostasis.
Area of Science:
- Physiology
- Developmental Biology
- Cardiovascular Science
Background:
- Preterm birth elevates adult cardiometabolic disease risk.
- Infants born prematurely face sodium depletion due to immature kidneys.
- Hypothalamic development is critical during the second trimester, a period vulnerable to sodium imbalance.
Purpose of the Study:
- To investigate if early-life sodium restriction programs long-term changes in cardiovascular autonomic control.
- To determine the impact of early sodium intake on autonomic nervous system regulation of cardiovascular function.
- To explore the role of the renin-angiotensin system (RAS) in mediating these programming effects.
Main Methods:
- Male mice were fed low (0.04%) or normal (0.30%) sodium diets during a critical hypothalamic development window (postnatal days 21-42).
- Hemodynamic and autonomic functions were assessed via radiotelemetry after switching to a high sodium diet (1%) and treatment with losartan.
- Autonomic antagonists were used to evaluate cardiovascular responses to sympathetic and parasympathetic blockade.
Main Results:
- Early sodium restriction led to altered hemodynamic responses to autonomic blockade on a standard diet.
- High sodium diet increased systolic blood pressure in previously sodium-restricted mice, with heightened cardiac sympathetic activity.
- Losartan, an angiotensin II type 1 receptor antagonist, demonstrated a greater blood pressure-lowering effect in sodium-restricted mice.
Conclusions:
- Sodium restriction during a critical hypothalamic developmental period programs lasting alterations in autonomic cardiovascular control.
- This programming may contribute to the increased risk of salt-sensitive hypertension and cardiovascular disease observed in former preterm infants.
- Maintaining postnatal sodium homeostasis is crucial for preventing renin-angiotensin system dysregulation and associated long-term cardiovascular risks.
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 [postnatal day (PD)21-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 to 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 wk of age. Mice were additionally treated with the angiotensin II type 1 receptor antagonist losartan for 2 wk. On standard diet, early-life Na restriction resulted in small but significantly different hemodynamic responses to autonomic blockers without any effect on systolic blood pressure (SBP) or heart rate. 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 that Na restriction during a critical hypothalamic developmental period programs long-term changes in the autonomic control of cardiovascular functions and may offer insight into the increased risk of cardiovascular disease in former preterm infants.NEW & NOTEWORTHY Mechanisms by which preterm birth increases the risk of adult-onset cardiometabolic diseases are not well understood. The renin-angiotensin system (RAS) has been implicated in the programming of adult disease, although contributors to RAS dysregulation remain to be identified. Findings from this study suggest that failure to maintain postnatal sodium homeostasis during a critical developmental window may contribute to RAS dysregulation and the risk of salt sensitivity of autonomic and cardiovascular function.
