Role of angiotensin II in chronic intermittent hypoxia-induced hypertension and cognitive decline

Abstract

Sleep apnea is characterized by momentary interruptions in normal respiration and leads to periods of decreased oxygen, or intermittent hypoxia. Chronic intermittent hypoxia is a model of the hypoxemia associated with sleep apnea and results in a sustained hypertension that is maintained during normoxia. Adaptations of the carotid body and activation of the renin-angiotensin system may contribute to the development of hypertension associated with chronic intermittent hypoxia. The subsequent activation of the brain renin-angiotensin system may produce changes in sympathetic regulatory neural networks that support the maintenance of the hypertension associated with intermittent hypoxia. Hypertension and sleep apnea not only increase risk for cardiovascular disease but are also risk factors for cognitive decline and Alzheimer's disease. Activation of the angiotensin system could be a common mechanism that links these disorders.

Keywords: GABA; SA; SNA; angiotensin II; hypertension; sleep apnea; sympathetic nerve activity.

Figure 1.

Chronic intermittent hypoxia induces hypertension through increased sympathetic nerve activity and angiotensin II (ANG II). Sagittal view of the rat brain illustrating initiation of hypertension due to chronic intermittent hypoxia (CIH), leading to an increase in sympathetic nerve activity (SNA) and plasma renin activity via the nucleus of the solitary tract (NTS) and rostral ventrolateral medulla (RVLM). The subfornical organ (SFO) is a primary target in modulating central actions of ANG II. As ANG II concentration increases, the SFO is stimulated (green lines) and projects to the MnPO and paraventricular nucleus (PVN) in the forebrain. The PVN projects to the NTS and RVLM in the hindbrain to increase sympathetic outflow through the intermediolateral column of the spinal cord (IML) and sustain hypertension (black lines). The NTS also provides input to the PVN (blue line). MnPO, median preoptic nucleus (Created with BioRender.com).

Figure 2.

Angiotensin II increases chloride flux through NKCC1, which drives an inward depolarization and GABA_A receptor disinhibition. A: intracellular [Cl⁻] is normally balanced through ion influx and efflux via sodium-potassium-chloride exchanger 1 (NKCC1) and potassium-chloride exchanger 2 (KCC2), respectively. B: angiotensin II (ANG II) can facilitate increases in Cl⁻ influx through NKCC1 causing a reversal potential that results in an inward depolarization. Thus, GABA_A receptor-mediated depolarizations can contribute to action potential generation and voltage-gated Ca²⁺ channel activation that enhance the excitability of the neurons. Overall, there is an increase in intracellular [Cl⁻] and intracellular [Ca²⁺], and an excitatory response that diminishes GABAergic inhibition. Blue lines indicate cation movement; red lines indicate anion movement. KCC2, potassium-chloride cotransporter 2.

Figure 3.

Sleep apnea, the renin-angiotensin system, and cognitive decline. Flowchart outlining how intermittent hypoxia characteristic of sleep apnea leads to increased activity of both the peripheral and brain renin angiotensin systems (RAS), resulting in a feedforward loop of hypertension and oxidative stress, that contributes to cognitive decline.