Median Preoptic AT1a Receptor Increase Responsible for Sustained Component of Hypertension from Chronic Intermittent Hypoxia




Shell, Brent
Nedungadi, T. Prashant
Cunningham, J. Thomas


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Sleep apnea sufferers experience repeated bouts of hypoxemia that result in a sustained increase in blood pressure. This hypertension persists despite the cessation of the hypoxic stimulus. Our lab focuses on a model for the hypoxemia experienced during sleep apnea by exposing rodents to chronic intermittent hypoxia (CIH). Previous studies have shown that there is an increase in neuronal activity in regions of the brain associated with sympathetic nerve activity after CIH, but little is known about the specific maladaptive neural changes that occur to drive this pathophysiology. Work from our lab has shown that the Angiotensin II Type 1a Receptor (AT1aR) is up regulated after CIH in the Median Preoptic Nucleus (MnPO). The MnPO receives inputs from circumventricular organs outside the blood brain barrier and synapses on regions controlling sympathetic outflow. This critical location between peripheral sensation neurons and downstream effector neurons makes the MnPO an attractive target for intervention. We hypothesize that CIH results in up-regulation of AT1aRs in the MnPO and results in excessive activation of downstream neurons responsible for sympathetic activation and sustained hypertension. Sprague-Dawley rats receive microinjections of a virus with a short hairpin RNA that binds to the AT1a receptor (AT1ashRNA) RNA or a scramble sequence (SCRshRNA) in the MnPO. After recovery, radio telemetry is implanted for continuous monitoring of cardiovascular variables. Rats proceed through a CIH protocol consisting of a 5 day baseline followed by a 7 days of CIH. On the morning of the 8th day animals are perfused for FosB immunohistochemistry (IHC) or snap frozen for qRT-PCR. Exposure to CIH resulted in a significant increase in AT1aR mRNA in the MnPO which was prevented by of AT1ashRNA.The ability of AT1ashRNA to eliminate the sustained component of hypertension by preventing the increase in AT1aR RNA demonstrates the importance of Ang II MnPO in this type of neurogenic hypertension. The ability of this signaling to influence downstream sympathetic outflow as shown by a lack of FosB IHC in the RVLM provides insight into the mechanism of this disease. These experiments can help us to optimize our current sleep apnea treatment regimen by focusing on blood brain barrier permeable angiotensin receptor blockers as well as provide new therapies for neurogenically derived hypertension.


Research Appreciation Day Award Winner - 2015 Smith and Nephew - 2nd Place Translational Research Award
Research Appreciation Day Award Winner - 2015 Cardiovascular Research Institute Award Presentation - 2nd Place Graduate Student