Mice Exposed to Maternal Separation are Resilient to the Loss of Circadian Heart Rate Rhythm in Response to Chronic High Salt Diet

Abstract

Early life stress (ELS) is associated with increases in body mass index and systolic blood pressure in adult life, leading to obesity and obesity‐induced hypertension, major risk factors for cardiovascular disease (CVD). Previously, we have shown that Maternal Separation and Early Weaning (MSEW), a model that mimics the effects of ELS in humans, increases blood pressure and sympathetic activation in obese male mice. We have also shown that MSEW males fed a low‐fat diet (LF) displayed increased water intake, urine excretion, potassium excretion, glomerular filtration rate (GFR), and renal cortex NHE3 expression compared to controls. The aim of this study was to further investigate the status of the water and electrolyte homeostasis (WEH) when we challenge mice exposed to MSEW with a chronic high‐salt diet (HS). C57BL/6J mice pups were separated from the dams from postnatal day (PD) 2 to PD 16 and weaned early on PD 17. Control (C) litters remained undisturbed with the dams and were weaned on PD 21. At weaning, mice were placed on a LF (10% Kcal from fat, Research Diets). After 18 weeks, mice were implanted with radiotelemeters to measure systolic blood pressure (SBP) and heart rate (HR). At 20 weeks, a baseline was recorded and then mice were placed on a LF+HS (10% Kcal from fat, 4% NaCl, Research Diets) for 6 weeks. Single mouse metabolic cages were used to measure water intake and urine excretion before and after LF+HS. GFR was measured using a transcutaneous technique. After 6 weeks, control and MSEW mice showed a similar response to LF+HS in water intake (3.84 ± 0.54 vs. 4.56 ± 1.01 ml), urine excretion (1.90 ± 0.93 vs. 2.63 ± 1.18 ml), and GFR (930.98 ± 41.30 vs. 975.97 ± 86.12 ml/min/100g BW). In addition, 6 weeks of LF+HS did not change 24‐hr SBP from baseline in control (125.5 ± 5.85 vs. 129.33 ± 6.0 mmHg) and MSEW mice (117.33 ± 9.55 vs. 126.67 ± 11.98 mmHg). Similarly, HR did not change in control (612.88 ± 19.51 vs. 651.67 ± 17.84 bpm) and MSEW mice (602.25 ± 15.27 vs. 575.83 ± 11.24 bpm). At baseline, both groups show normal circadian rhythm of blood pressure. However, LF+HS control males lack day‐night HR amplitude (day: 655 ± 14.50 vs. night: 647.67 ± 11.17 bpm, p=NS) while MSEW mice preserve this function (day: 557.67 ± 6.97 mmHg vs. night: 594 ± 5.51 bpm, p<0.05). These data indicate that MSEW male mice are resilient to loss of circadian HR rhythm in response to a chronic HS. Ongoing studies of renal sodium transporters expression may provide insights into the potential mechanisms by which MSEW male mice display this resilience.