Prenatal Dexamethasone Programs Female-Biased Autonomic Dysregulation
Authors: Madhavpeddi Lakshmi , Madhavpeddi Lakshmi , Hale Taben 
Published: May 2023

Late gestation exposure to dexamethasone (DEX) results in female-specific elevations in stress-responsive blood pressure and heart rate as well as changes in heart rate variability (HRV) in adulthood, suggesting a role for glucocorticoid-mediated programming of autonomic function. The present study investigated the relative changes in sympathetic (SYM) or parasympathetic (PS) activities that mediate sex-selective alteration in autonomic function using adrenergic (SYM) or cholinergic (PS) antagonists. Naïve breeders were exposed to DEX (0.4mg/kg/day, s.c.) or vehicle (Veh) on gestation days 18-21. At 8-9 weeks offspring were instrumented with radiotelemetric transmitters for recording of HR and HRV. To evaluate the relative contribution of SYM and PS involvement, we examined the low frequency (LF; 0.20-0.75 Hz) and high frequency (HF; 0.75–2.00 Hz) components of HRV. LF is associated with SYM and PS activity, and HF with PS activity. At 10-11 weeks rats were administered either SYM antagonists, α-adrenoceptor (prazosin; 0.5mg/kg, i.p.) + β-adrenoceptor (atenolol; 1mg/kg, i.p.), PS, muscarinic (homatropine methylbromide; 0.2mg/kg, i.p), antagonist, or saline (CTR, i.p.). Assessments were made over 20 min following injection and then during a 20 min restraint test. Females were tested on diestrus. With respect to HRV, LF was not altered by sex or DEX exposure. HF was significantly reduced in DEX-exposed females and males. When rats were administered SYM antagonists, LF (p<0.0001) and HF (p<0.001) were significantly reduced compared to CTR and this effect was independent of in utero DEX or sex. With PS antagonism, LF (p<0 .0001) and HF (p<0.0001) were significantly reduced compared to saline injection. When comparing the relative impact of SYM vs. PS antagonism, there is a tendency towards a 3-way interaction (p=0.067) indicating both sex and in utero DEX influence the degree of change in LF in response to antagonists. In response to SYM vs. PS antagonists, there is overall a significantly greater reduction in HF in Veh compared to DEX rats. Area under the curve analysis revealed that in female rats, compared to saline injection (CTR), SYM antagonism resulted in a greater reduction in HR in DEX-exposed rats, compared to Veh, at baseline (Veh -57%, p>0.05; DEX -73%, p<0.05) and during restraint (Veh -55%, p>0.05; DEX -70%, p<0.05). In contrast, PS antagonism elevated HR to a greater degree in female rats exposed to Veh in utero both at baseline (Veh +92%, p<0.05; DEX +84%, p>0.05) and during restraint (Veh +49%, p<0.05; DEX -4%, p>0.05). In males, in utero DEX exposure did not impact the responsiveness to SYM or PS antagonism in adulthood. These findings reveal that in utero exposure to DEX disrupts the autonomic function of female rats. Pharmacological antagonists revealed that Veh-exposed females show a greater reliance on PS at rest and in response to restraint, and that this is altered in DEX-exposed females who show a shift toward SYM dominance. NIH U54 MH118919 This is the full abstract presented at the American Physiology Summit 2023 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.