The apneic threshold during non-REM sleep in dogs: sensitivity of carotid body vs. central chemoreceptors

Abstract

The relative importance of peripheral vs. central chemoreceptors in causing apnea/unstable breathing during sleep is unresolved. This has never been tested in an unanesthetized preparation with intact carotid bodies. We studied three unanesthetized dogs during normal sleep in a preparation in which intact carotid body chemoreceptors could be reversibly isolated from the systemic circulation and perfused. Apneic thresholds and the CO(2) reserve (end-tidal Pco(2) eupneic - end-tidal Pco(2) apneic threshold) were determined using a pressure support ventilation technique. Dogs were studied when both central and peripheral chemoreceptors sensed transient hypocapnia induced by the pressure support ventilation and again with carotid body isolation such that only the central chemoreceptors sensed the hypocapnia. We observed that the CO(2) reserve was congruent with4.5 Torr when the carotid chemoreceptors sensed the transient hypocapnia but more than doubled (>9 Torr) when only the central chemoreceptors sensed hypocapnia. Furthermore, the expiratory time prolongations observed when only central chemoreceptors were exposed to hypocapnia differed from those obtained when both the central and peripheral chemoreceptors sensed the hypocapnia in that they 1) were substantially shorter for a given reduction in end-tidal Pco(2), 2) showed no stimulus: response relationship with increasing hypocapnia, and 3) often occurred at a time (>45 s) beyond the latency expected for the central chemoreceptors. These findings agree with those previously obtained using an identical pressure support ventilation protocol in carotid body-denervated sleeping dogs (Nakayama H, Smith CA, Rodman JR, Skatrud JB, Dempsey JA. J Appl Physiol 94: 155-164, 2003). We conclude that hypocapnia sensed at the carotid body chemoreceptor is required for the initiation of apnea following a transient ventilatory overshoot in non-rapid eye movement sleep.

Central Chemoreceptors: Locations and Functions

“…This study shows clearly that NTS activation by carotid body stimulation also activates RTN neurons that are chemoresponsive to CO 2 . These data support the concept of a functional interdependence between central and peripheral chemoreception (19, 231) (vida infra).…”

“…The remaining response (~40% of the original) must arise elsewhere, either at other central chemoreceptor sites or at the carotid body. The degree of participation of the carotid body is likely compromised based on the data of Takakura et al (250) showing that carotid body afferent traffic travels in part through the RTN as well as the recent data supporting interdependence between central and peripheral chemoreceptors (19, 231). …”

“…This approach along with the use of various inspired gas mixtures and applied artificial ventilation has allowed separation of the two systems without the problems of adaptation associated with denervation or lesions. This work has been recently review (70, 231). Two main concepts have emerged: (i) interdependence, and (ii) the importance of hypocapnia.…”

Chronic intermittent hypoxia reduces ventilatory long-term facilitation and enhances apnea frequency in newborn rats

“…This could help to understand the well-known inverse relationship between apnea frequency and gestational age at birth in preterm neonates (26). An additional factor emerges from the fact that CIH enhances hypoxic chemoreflex, promoting potent "overshoot" responses to hypoxemic exposure, and further contributing to enhance apnea, as previously suggested (2,11,41,49), particularly when the protective mechanisms of LTF are not present or have been impaired (present study). Since ventilatory LTF development is delayed by CIH, apneas should then persist for a longer period of time during postnatal life reflecting the delayed development of protective mechanism.…”

“…It has been previously suggested that elevated hypoxic sensitivity of peripheral chemoreceptors may be critical to generate apneas, specifically in preterm neonates (2,11,41), consistently with the well-supported role of peripheral chemoreceptors on generation of apneas (17,49). But the existence of a relationship between hypoxic sensitivity and apnea frequency is not commonly tested in experimental studies.…”