Airway obstruction produces widespread sympathoexcitation: role of hypoxia, carotid chemoreceptors, and NTS neurotransmission

Abstract

Obstructive sleep apnea (OSA) is the most common respiratory disturbance of sleep and is closely associated to cardiovascular diseases. In humans, apnea increases respiratory effort and elevates muscle sympathetic nerve activity (SNA), but the primary stimulus for the SNA activation has not been identified. We recently developed a model of apnea in rodents using acute airway obstruction. In this study, we employed this model to test whether the elevation in SNA was mediated by hypoxia, carotid chemoreceptors, or neurotransmission in the nucleus tractus solitarius (NTS). In anesthetized, male Sprague–Dawley rats, airway obstruction (20s) increased phrenic nerve activity (PNA), arterial blood pressure (ABP), and lumbar, renal, and splanchnic SNA. The changes in SNA were similar across all three sympathetic nerves. Inactivation of chemoreceptors by hyperoxia (100% O2) or surgical denervation of carotid chemoreceptors attenuated, but did not eliminate, the changes in SNA and ABP produced by airway obstruction. To interrupt afferent information from carotid chemoreceptor and extracarotid afferents to the hindbrain, airway obstruction was performed before and after NTS microinjection of the GABAA agonist muscimol or a cocktail of NMDA and non‐NMDA antagonists. Inhibition of NTS neurons or blockade of glutamatergic receptors attenuated the increase in lumbar SNA, splanchnic SNA, renal SNA, and PNA. Collectively, these findings suggest that PNA and SNA responses induced by airway obstruction depend, in part, on chemoreceptors afferents and glutamatergic neurotransmission in the NTS.

Autonomic regulation during sleep and wakefulness: a review with implications for defining the pathophysiology of neurological disorders

“…Mokhlesi and colleagues demonstrated a dose–response risk for developing systolic and diastolic non-dipping BP with increasing severity of sleep apnea [61]. Experiments in rats have demonstrated how repetitive apneas have an additive effect on widening pulse pressure and increasing BP; these responses activate CNS ascending arousal systems, increase respiratory muscle effort, cause changes in intrathoracic blood volume, and activate sympathetic activity [59, 60, 62]. Data from rat models of chronic intermittent hypoxia have also provided evidence for renal mechanisms in the development of chronically elevated BP.…”

Testing of novel spectral device sensor in swine model of airway obstruction

“…We hypothesized that both slow‐ and rapid‐onset obstruction would increase MAP (via sympathoexcitation) (O'Donnell et al, ; Ferreira et al, ). Indeed, this occurred in 56% (9/16) of animals, while in 44% (7/16) MAP was decreased in response to airway obstruction.…”

Is Aberrant Reno-Renal Reflex Control of Blood Pressure a Contributor to Chronic Intermittent Hypoxia-Induced Hypertension?

“…In addition, heart rate variability was progressively exaggerated in CIH-exposed rats after the 7th day of exposure but was restored to normal following surgical ablation of the carotid bodies (Del Rio et al, 2016). In contrast, carotid body denervation partially attenuated the increase in sympathetic activity and heart rate observed after acute upper airway obstruction (Ferreira et al, 2018). Moreover, administration of 100% oxygen to silence the activity of carotid bodies during upper airway obstruction reduced, but did not eliminate the increase in sympathetic nerve activity.…”

“…These results suggest that carotid body afferents partially contribute to sympathoexcitation during apnoea (hypoxic hypercapnia). Inhibition of NTS neurons reduced phrenic, renal, lumbar, and splanchnic nerve activity and heart rate during upper airway obstruction (Ferreira et al, 2018). However, the influence of central chemoreceptor inputs to SNS activity is likely important during upper airway obstruction as CO 2 and hydrogen ions activate chemosensitive sites, which leads to sympathoexcitation and resultant cardiorespiratory changes.…”