Neural Control of Blood Pressure in Chronic Intermittent Hypoxia

Abstract

Sleep apnea (SA) is increasing in prevalence and is commonly comorbid with hypertension. Chronic intermittent hypoxia is used to model the arterial hypoxemia seen in SA, and through this paradigm, the mechanisms that underlie SA-induced hypertension are becoming clear. Cyclic hypoxic exposure during sleep chronically stimulates the carotid chemoreflexes, inducing sensory long-term facilitation, and drives sympathetic outflow from the hindbrain. The elevated sympathetic tone drives hypertension and renal sympathetic activity to the kidneys resulting in increased plasma renin activity and eventually angiotensin II (Ang II) peripherally. Upon waking, when respiration is normalized, the sympathetic activity does not diminish. This is partially because of adaptations leading to overactivation of the hindbrain regions controlling sympathetic outflow such as the nucleus tractus solitarius (NTS), and rostral ventrolateral medulla (RVLM). The sustained sympathetic activity is also due to enhanced synaptic signaling from the forebrain through the paraventricular nucleus (PVN). During the waking hours, when the chemoreceptors are not exposed to hypoxia, the forebrain circumventricular organs (CVOs) are stimulated by peripherally circulating Ang II from the elevated plasma renin activity. The CVOs and median preoptic nucleus chronically activate the PVN due to the Ang II signaling. All together, this leads to elevated nocturnal mean arterial pressure (MAP) as a response to hypoxemia, as well as inappropriately elevated diurnal MAP in response to maladaptations.

Keywords: Chronic intermittent hypoxia (CIH); Hypertension; Sleep apnea (SA); Sympathetic nerve activity (SNA).

Fig. 1

Hypertension Initiation—The hypoxemia from CIH or sleep apnea drives the activation of the carotid bodies. This in turn activates the NTS and the RVLM to increase sympathetic tone. In addition, the sympathetic outflow to the kidneys increases plasma renin activity (PRA) and results in increased circulating angiotensin II (Ang II) during both the hypoxic period and later during the normoxic period. Hypertension Maintenance—Circulating Ang II activates SFO which synapses and activates MnPO. Both of these nuclei stimulate the PVN. The NTS also has afferent connections to PVN that could converge with excitation from the SFO and MnPO. Together with enhanced activity from the NTS due to altered chemoreceptor function, these forebrain mechanisms could contribute to the maintenance of the hypertension during the normoxic periods of CIH