Circadian Stress Increases Hypertension Sensitivity in Male Rats

Early life stress (ELS) leads to a greater risk of hypertension, but no studies have specifically examined stress produced by circadian disruption. We hypothesize that circadian stress during adolescence will increase sensitivity to a hypertensive stimulus in adulthood recapitulating other models of ELS. We exposed male and female Sprague-Dawley rats 1-2 weeks post-weaning to 6-hour phase advances in the light/dark cycle every 4 days for 4 weeks; controls were maintained in consistent 12h light/dark periods. At 11-12 weeks of age, baseline mean arterial pressure (MAP) was measured (telemetry) followed by a 2-wk angiotensin II (Ang II) infusion (250 ng/kg/min, s.c.). At baseline, control and early circadian stressed (ECS) rats of both sexes had no significant differences in MAP suggesting that exposure to circadian stress early in life has no effect on baseline MAP. Male ECS rats had a faster rise in MAP after 4 days of AngII infusion (p ECS =0.023, p AngII =<0.001, p ECSxAngII =0.047). However, by the end of the 14-day Ang II infusion period, MAP levels of ECS male rats became comparable to controls, suggesting heightened sympathetic activity in male ECS rats. In contrast, female ECS rats had an attenuated MAP response to AngII compared to controls (p ECS =0.058, p AngII =0.001, p ECSxAngII =0.171). We also observed a significant phase advance in peak MAP time in male ECS rats that was absent in controls (p ECS =0.039, p AngII <0.001, p ECSxAngII =0.002). There were no significant differences in rhythmicity or peak MAP time of either female group. Baseline heart rate (HR) of control and ECS of either sex was not significantly different. However, ECS males had an increased HR after 5 days of AngII infusion (p ECS =0.059, p AngII =0.486, p ECSxAngII =0.094, 2-key post hoc comparison p=0.013), further suggesting heightened sympathetic activity. Females had no change in HR regardless of stress or Ang II. We propose that circadian stress during the post-weaning period increases sensitivity to Ang II in a sex-specific manner.