The mechanisms behind the central RAS and secondary hypertension in chronic intermittent hypoxia

Abstract

Research Question: This study further examines the emerging role of the central renin- angiotensin system (RAS), specifically the angiotensin type 1 (AT1a) receptor in the median preoptic nucleus (MnPO), in the development of hypertension (HTN), particularly using the model of chronic intermittent hypoxia (CIH). To that end, this study addresses the question, “In rats with an elimination of AT1a receptors that are active in the central RAS within the MnPO, will the sustained HTN experienced secondary to CIH be reduced as compared to rats with these receptors active?”.

Background, Significance, and Rationale: Recent studies have shown the involvement of the central RAS in the development of the chronic HTN, specifically through the activation of AT1a receptors in the MnPO. Additionally, CIH as seen in obstructive sleep apnea (OSA) has been well-characterized as a leading factor contributing to the development of secondary HTN, or HTN that can be attributed to another medical condition and thus is best treated by resolving the primary pathology. One cortical area, the MnPO, has been implicated in the activity of the central RAS and subsequent development of sustained HTN in the setting of CIH. AT1a receptors are found in this area and previous studies have shown that viral knockdown of these receptors attenuates the increases in blood pressure associated with CIH. Thus, determining the answer to this research question would provide clarity on the processes underlying HTN associated with central RAS signaling and provide new potential therapeutic targets for secondary HTN associated with OSA.

Materials and Methods: This study was conducted utilizing existing protocols to induce selective knockout of the AT1a receptor in the MnPO using a CIH model to mimic OSA. These studies were performed using an animal model and in-vitro patch recordings to monitor spontaneous excitation and inhibition in response to various stimuli.

Results: There was shown to be a relationship between CIH and the AT1a receptor in modulating excitation and inhibition in the MnPO. Recordings from the CIH model showed impaired duration of angiotensin II-mediated MnPO excitation. Additionally, both CIH and AT1a blockade impaired gamma aminobutyric acid (GABA)-mediated inhibition, while the two paired together produced GABA-mediated excitation.

Conclusions: The current study suggests that CIH attenuates GABA-mediated inhibition through the activity of the AT1a receptor in the MnPO, a process which may underlie the sustained HTN seen with CIH.