A Vital role for Median Preoptic AT1a Receptors in the Sustained Hypertension of Chronic Intermittent Hypoxia

Purpose The hypoxemia from Sleep Apnea (SA) results in hypertension during both the hypoxic sleeping period and the normoxic waking period. This pathophysiological sustained hypertension persists during waking hours and is a source of numerous cardiovascular sequlae. In order to better understand the neurological changes that underlie this disease state, our lab utilizes Chronic Intermittent Hypoxia (CIH) to model the hypoxemia and generate the hypertension of SA sufferers. Previously, our lab has shown that the Median Preoptic Nucleus increases in both neuronal activity and Angiotensin Type 1a Receptor (AT1aR) RNA expression in response to CIH. The MnPO is situated in a critical location that allows it to receive inputs from nuclei outside of the blood brain barrier and provide inputs to regions that control sympathetic outflow, and therefore blood pressure. The ability to modulate sympathetics based upon peripheral inputs coupled with increased activity and AT1aR expression leads us to hypothesize that increased Angiotensin signaling to the MnPO is essential for the sustained component of hypertension from CIH. Methods Male Sprague-Dawley rats were microinjected in the MnPO with either a virus to knockdown AT1aR expression (shAT1a) or a scramble virus (SCR) and instrumented with radio telemetry a week later. Radio telemetry provides continuous recording of cardiovascular variables. After a week of surgery recovery the animals were monitored for a 5 day baseline period before experiencing 7 days of CIH. The morning of the final day, the animals were either perfused with formaldehyde for immunohistochemistry (IHC) or their brains were snap frozen for quantitative PCR. Results Rodents injected in the MnPO with the shAT1a did not exhibit the sustained component of hypertension compared to SCR animals (P Conclusions Overall, this data indicates that the increase in AT1aR expression in the MnPO is essential for the development of the sustained component of CIH hypertension. The shAT1a virus successfully prevents the increase in AT1aR expression and this leads to normal waking blood pressure in the CIH exposed rodents. IHC results indicate that there is less activity in the MnPO and RVLM of the rodents most likely related to reduced sympathetic outflow. This data lends support to optimizing our current treatment regiment through blood brain barrier AT1aR blockers and ACE inhibitors. Future treatment methods could focus solely on preventing Angiotensin as a peptide neurotransmitter in the MnPO to ameliorate neurogenic hypertension.