Carotid body potentiation induced by intermittent hypoxia: Implications for cardiorespiratory changes induced by sleep apnoea

Abstract

1. The most usual form of chronic hypoxia in humans is the intermittent hypoxia resulting from obstructive sleep apnoea (OSA). The OSA syndrome is a highly prevalent sleep breathing disorder that is considered an independent risk factor for hypertension and cardiovascular diseases. Endothelial dysfunction, oxidative stress, inflammation and sympathetic activation have been proposed as potential mechanisms involved in the onset of the hypertension. However, evidence for a unique pathogenic mechanism has been difficult to establish in OSA patients because of concomitant comorbidities. Thus, animal models have been developed to study the pathological consequences of exposure to chronic intermittent hypoxia (CIH). 2. Because OSA patients and animals exposed to CIH show augmented ventilatory, sympathetic and cardiovascular responses to acute hypoxia, it has been proposed that enhanced carotid body responsiveness to hypoxia is involved in the autonomic changes induced by OSA and in the development of the hypertension. Recently, this proposal has received further support from recordings of carotid body chemosensory neural discharges in situ and in vitro showing that exposure of animals to CIH increases basal carotid body chemosensory discharges and enhances the chemosensory response to hypoxia. 3. In the present brief review, we discuss the evidence supporting an important role for the carotid body in the progression of cardiorespiratory changes induced by OSA and the contribution of oxidative stress, endothelin-1 and pro-inflammatory molecules in the potentiation of the carotid body chemosensory function induced by CIH.

Oxidative Stress in the Carotid Body: Implications for the Cardioventilatory Alterations Induced by Obstructive Sleep Apnea

“…The increased formation of 3-nitrotyrosine indicates that the carotid body tissue is continuously exposed to oxidative stress during the intermittent hypoxic exposure. In addition, we found that a correlation between the marked increase of 3-nitrotyrosine immunoreactivity in the carotid body exposed to intermittent hypoxia and the enhanced carotid chemosensory responses to acute hypoxia (Del Rio et al, 2011), supporting and extending the idea that oxidative-nitrosative stress plays a critical role in the CB chemosensory potentiation (Iturriaga et al, 2009. In OSA patients, Jelic et al, (2008) found that the expression of 3-nitrotyrosine in endothelial cells was greater than controls subjects, indicating that the oxidative stress contributes to the endothelial dysfunction caused by the intermittent hypoxia.…”

“…The enhance carotid chemosensory responses to hypoxia has been associated to increased levels of reactive oxygen species , Iturriaga et al, 2009, Del Rio et al, 2010 and endothelin-1 within the CB (Rey et al, 2006, Pawar et al, 2009, but it is possible that pro-inflammatory cytokines, which increased in the plasma of OSA patients (Lavie 2003, Jelic et al, 2008 may also contributes to the enhanced carotid body chemosensory responses to acute hypoxia (Iturriaga et al, 2009;Del Rio et al, 2011). Although some studies addressed the effects of intermittent hypoxia on transmitter production and release in the carotid body, very little is known on the functional significance of the role played by the neurotransmitters in the carotid body chemosensory potentiation induced by intermittent hypoxia (See for review Kumar, 2011).…”

“…Thus, the available evidence supports the proposal that the enhanced oxygen chemoreflex response in OSA patients is produced by the intermittent hypoxia. Similarly, rats and cats exposed to chronic intermittent hypoxia show enhanced hypoxic ventilatory responses to acute hypoxia (Iturriaga et al, 2009Reeves et al, 2003) and long-term facilitation of respiratory motor responses (McGuire et al, 2003, Dick et al, 2007, Prahbakar et al, 2005. The long-term potentiated ventilatory responses to acute hypoxia observed in animals exposed to intermittent hypoxia has been attributed to a central facilitation of the serotonin-mediated motor ventilatory output (McGuire et al, 2003).…”

Carotid sinus nerve stimulation, but not intermittent hypoxia, induces respiratory LTF in adult rats exposed to neonatal intermittent hypoxia

“…In adults, this depends on the recurrent activation of peripheral chemoreceptors and is prevented by bilateral carotid body denervation during exposure (12,30), and following chemical sympathetic denervation (13). This is accompanied by an enhanced activity of peripheral chemoreceptors (23,48), chronic sympathetic activation (11,29,31,44), blunted baroreflex responses (3,31), and functional changes in the vascular bed (7). Whether similar changes are also induced by exposure to neonatal hypoxia in newborns and have longlasting effects remains to be documented.…”

Contribution of Autonomic Nervous System to the Hypertension Induced by Obstructive Sleep Apnea

“…The primary oxygen sensors in the carotid body are the glomus cells, which are in synaptic contact with the nerve terminals of the chemosensory petrosal neurons [31,40,42]. The current model of chemoreception states that hypoxia induces the inhibition of voltage-independent tandem pore domain potassium channels (TASK K + ), leading to the depolarization of the glomus cells, the entry of Ca 2+ through L-type Ca 2+ channels, and the subsequent release of excitatory transmitters (Acetylcholine and adenosine triphosphate), which increases the discharges of the nerve endings of the petrosal chemosensory neurons [40,42]. Recently, we found that chronic intermittent hypoxia potentiates the hypoxic inhibition of the TASK-like K + channel currents in glomus cells from intermittent hypoxia rats.…”