Impact of Prenatal Dexamethasone on Adult Cardiovascular Autonomic Regulation
Authors: Madhavpeddi Lakshmi , Hammond Bradley , Carbone David , Handa Robert J , Hale Taben M 
Published: April 2020

It is well established that even transient prenatal insults can impact cardiovascular (CV) function in adulthood. We hypothesized that adult CV disease may have its origins in utero as a result of exposure to elevated levels of glucocorticoids arising as a result of prenatal stress or inflammation. In support of this, we showed that when pregnant rat dams are treated with the synthetic glucocorticoid, dexamethasone (DEX), for 4 days in late gestation, there are female‐specific changes resulting in enhanced pressor and tachycardic responses to stress in adult offspring. We further showed that these effects in DEX exposed females can be reversed following treatment with the angiotensin II type 1 receptor antagonist, losartan. To better understand whether autonomic imbalance drives the sex‐specific CV effects of adult offspring prenatally exposed to DEX, we investigated the impact of DEX on heart rate variability (HRV). Pregnant dams were administered DEX (0.4mg/kg per day, s.c.) or vehicle on gestation days 18–21. This resulted in a significant reduction in birthweight in DEX‐exposed males and females. At 2–3 months of age, rats were instrumented with radiotelemetric transmitters for direct recording of arterial pressure, heart rate, and HRV. In a separate cohort, female rats were re‐evaluated following 9 days of losartan (30mg/kg per day, i.p.). HRV was analyzed in the frequency domain by obtaining arterial pressure waveforms recorded over 2–3 days. Interbeat intervals were analyzed (Kubios Software), and a fast fourier transformation was performed and data integrated into two frequency bands: low frequency (LF: 0.20–0.75 Hz) and high frequency (0.75–2.00 Hz). The LF component represents both the sympathetic (SYM) and parasympathetic (PS) input, while the HF component corresponds to PS nervous system activity. The LF/HF ratio is used to assess relative SYM activity. Data were analyzed by Two Way ANOVA (sex x prenatal treatment). There was a significant effect of sex with females having greater HF power, and a significant interaction whereby HF power increased in males and decreased in females prenatally exposed to DEX. Neither sex nor prenatal DEX had any impact on LF power; however, there was a significant sex effect and interaction when assessing LF/HF. DEX decreased the ratio in males, but tended to increase it in females exposed to DEX, in utero. Losartan treatment in DEX exposed females significantly increased HF to a level that was not different from vehicle rats. The increased HF power in females suggests a greater reliance on PS drive than males. However, prenatal DEX exposure produces sex‐specific reductions PS drive in females, that is reversible by losartan treatment. This decrease in PS activity may underlie the altered pressor and tachycardic stress responses that we have previously observed in these rats. Additionally, these findings suggest that autonomic dysregulation following prenatal DEX may be mediated in part due to long‐term changes in central renin‐angiotensin signaling. Further studies will use SYM and PS antagonists to further elucidate the impact of DEX and sex on cardiac autonomic imbalance in the pursuit of examining the long‐term consequence of age‐ and sex‐related changes of DEX on CV function.Support or Funding InformationSpringboard, ABRC