Maternal Injection with Dexamethasone Results in Female-Biased Autonomic Dysregulation in Rat Offspring

Abstract

Autonomic dysfunction is an underlying risk factor for cardiovascular disease (CVD). Maternal injection of the synthetic GC dexamethasone (DEX) during the last 4 days of gestation results in female-biased increases in stress-responsive pressor (MAP), heart rate (HR) and altered heart rate variability (HRV) in adult rat offspring, suggesting a role for GC-mediated programming of autonomic function. The present study used pharmacological antagonists for adrenergic (SYM) or cholinergic (PS) receptors to investigate the degree to which changes in SYM or PS activity underlie the autonomic dysfunction in offspring of dams injected with DEX during late gestation. Naïve breeders were injected with DEX (0.4mg/kg/day, s.c.) or vehicle (hydroxypropyl beta cyclodextrin; Veh) on gestation days 18-21. Radiotelemetry was used in adult offspring for recording HR, MAP, and HRV (root mean square of successive differences: RMSSD). At 10-11 weeks rats were randomly assigned to receive SYM antagonists, α-adrenoceptor (prazosin; 0.5mg/kg, i.p.) + β-adrenoceptor (atenolol; 1mg/kg, i.p.), a PS antagonist (homatropine methylbromide; 0.2mg/kg, i.p), or saline (SAL, i.p.). Evaluations were made over 20 min following injection and then during a 20 min restraint. Females were tested on diestrus. In utero DEX exposure resulted in significantly lower RMSSD, an index of vagal tone, in DEX-exposed females and males. PS blockade significantly reduced RMSSD in Veh-, but not DEX-exposed female offspring. SYM blockade did not influence RMSSD in females. In males, PS blockade reduced in RMSSD in both DEX- and Veh-exposed offspring. SYM blockade only reduced RMSSD in males exposed to DEX. Area under the curve (AUC) analysis revealed that in female offspring, SYM blockade resulted in a greater reduction in HR in DEX-exposed offspring, compared to Veh (DEX-SYM: −220 bpm vs. DEX-SAL; Veh-SYM: −197 bpm vs. VEH-SAL) and during restraint (DEX-SYM: −535 bpm vs. DEX-SAL; Veh-SYM: −342 bpm vs. VEH-SAL). PS blockade resulted in a greater increase in HR in Veh-exposed females both following the injection (Veh-PS: −187 bpm vs. VEH-SAL; DEX-PS: −101 bpm vs. DEX-SAL) and during restraint (Veh-PS: −161 bpm vs. VEH-SAL; DEX-PS: −61 bpm vs. DEX-SAL). AUC analysis for MAP showed similar responses to those for HR with SYM blockade having a greater impact in DEX-exposed females and PS blockade having a greater effect in Veh-exposed females. By contrast, in male offspring in utero DEX exposure did not influence HR or MAP responses to SYM or PS blockade. Overall, these findings suggest that maternal DEX injections alter autonomic development primarily in in female offspring and is characterized by a shift from PS to SYM predominance. Better understanding of the mechanisms involved in this programming are important for identifying individuals at risk for CVD and development of interventional strategies for prevention of CVD. Funding: NIH U54 MH118919. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.