Carotid body function and ventilatory responses in intermittent hypoxia. evidence for anomalous brainstem integration of arterial chemoreceptor input

Abstract

Obstructive sleep apnea is a frequent medical condition consisting in repetitive sleep-related episodes of upper airways obstruction and concurrent events of arterial blood hypoxia. To this condition there is a frequent association of cardiovascular and other pathologies conforming the obstructive sleep apnea syndrome (OSAS). Laboratory models of OSAS consist in animals exposed repetitive episodes of Intermittent hypoxia (IH) which also develop cardiovascular pathology, mostly hypertension. The overall OSAS pathophysiology appears to be linked to the repetitive hypoxia, being proposed that it causes a sensitization of carotid body (CB) chemoreflex leading to a hyperreactivity of the sympathetic nervous system. However, this proposal is uncertain because normo or hypoventilation and normal plasma catecholamines are not infrequent findings in patients with OSAS and IH animals. Aiming to solve these issues we have studied in a rat model of IH the entire CB chemoreflex arch including activity of chemoreceptor cells and CB generated afferent activity to brainstem; efferent activity was measured as ventilation in normoxia, hypoxia and hypercapnia. Norepinephrine turnover in renal artery sympathetic endings was also assessed. Findings indicate a sensitization of the CB function to hypoxia evidenced by exaggerated chemoreceptor cell and CB afferent activity. At the same time IH rats exhibited marked hypoventilation in all studied conditions and increased turnover of norepinephrine in sympathetic endings. We conclude that IH causes a bias in the integration of the input arising from the CB with a diminished drive of ventilation and an exaggerated activation of brainstem sympathetic neurons. 2

Chronic intermittent hypoxia increases sympathetic control of blood pressure: role of neuronal activity in the hypothalamic paraventricular nucleus

“…This has been linked to sensitization of the arterial chemoreflex (15,32,45,50,67), which results from a complex mixture of mechanisms ranging from increased O 2 sensitivity of carotid body chemoreceptors (11,21,30,31,50) to enhanced sympathoexcitatory neurotransmission through the brain stem arterial chemoreflex arc (10,18,38,50,67). However, emerging evidence indicates that persistent neurogenic CIH hypertension involves additional adaptive mechanisms that contribute to heightened sympathetic drive.…”

The Carotid Body Does Not Mediate the Acute Ventilatory Effects of Leptin

“…General procedures used to label chemoreceptor cells 3 H-catecholamine ( 3 H-CA) (CA) deposits and later to study their release have been described in previous publications (Vicario et al 2000 ;Gonzalez-Martín et al 2011 ). And analytical methods have been described in detail in Conde et al ( 2006 ).…”

Chemoreflexes, Sleep Apnea, and Sympathetic Dysregulation

“…The chemoreflex is thought to play an important role [20, 26, 27, 97–101], although other mechanisms may contribute, as described below. Animal studies have indicated that the peripheral chemoreceptors located in the carotid body play a pivotal role in the response to hypoxia seen in OSA [102–109]. More recent analyses have demonstrated differential expressions of the various Hypoxia Inducible Factor (HIF) subtypes in the carotid body associated with local inflammation [110–112].…”