Role of Central/Peripheral Chemoreceptors and Their Interdependence in the Pathophysiology of Sleep Apnea

Dempsey, Jerome A.; Smith, Curtis A.; Blain, Grégory M.; Xie, Ailiang; Gong, Yabin; Teodorescu, Mihaela

doi:10.1007/978-94-007-4584-1_46

Cited by 78 publications

(49 citation statements)

References 30 publications

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“…The central respiratory chemoreflex is the breathing stimulation elicited by elevated brain PCO 2 (CNS hypercapnia); the peripheral chemoreflex is the breathing stimulation elicited by activation of the carotid bodies and related organelles (aortic bodies)(Dempsey et al, 2012; Kumar and Prabhakar, 2012). The carotid bodies are activated by arterial hypoxemia in a pH-dependent manner (i.e., blood acidification enhances the stimulatory effect of reduced PaO 2 ), by blood flow reduction and by increased blood concentration of lactate, potassium and catecholamine (Kumar and Prabhakar, 2012).…”

Section: Introductionmentioning

confidence: 99%

Neural Control of Breathing and CO2 Homeostasis

Guyenet

Bayliss

2015

Neuron

379

332

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Summary Recent advances have clarified how the brain detects CO2 to regulate breathing (central respiratory chemoreception). These mechanisms are reviewed and their significance is presented in the general context of CO2/pH homeostasis through breathing. At rest, respiratory chemoreflexes initiated at peripheral and central sites mediate rapid stabilization of arterial PCO2 and pH. Specific brainstem neurons (e.g., retrotrapezoid nucleus, RTN; serotonergic) are activated by PCO2 and stimulate breathing. RTN neurons detect CO2 via intrinsic proton receptors (TASK-2, GPR4), synaptic input from peripheral chemoreceptors and signals from astrocytes. Respiratory chemoreflexes are arousal state-dependent whereas chemoreceptor stimulation produces arousal. When abnormal, these interactions lead to sleep-disordered breathing. During exercise, “central command” and reflexes from exercising muscles produce the breathing stimulation required to maintain arterial PCO2 and pH despite elevated metabolic activity. The neural circuits underlying central command and muscle afferent control of breathing remain elusive and represent a fertile area for future investigation.

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Section: Introductionmentioning

confidence: 99%

Neural Control of Breathing and CO2 Homeostasis

Guyenet

Bayliss

2015

Neuron

379

332

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“…The apneas have been tentatively attributed to recurrent episodes of CNS hypocarbia that silence CRCs (Dempsey et al, 2012;Marcus et al, 2014). This interpretation agrees with the finding that respiratory alkalosis silences RTN in conscious rats (Basting et al, 2015).…”

Section: Introductionsupporting

confidence: 85%

Neural Control of Respiration by the Retrotrapezoid Nucleus.

Basting¹

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Rationale and objectives: Central respiratory chemoreceptors (CRCs) detect brain PaCO 2 and adjust lung ventilation to maintain PaCO 2 and pH constant regardless of the absolute level of lung ventilation. They perform this function in cooperation with the carotid bodies, sensory organs that respond to hypoxia in a pH-dependent manner. The existence of CRCs has been known for over a century but their cellular nature and location have remained highly controversial until recently. The retrotrapezoid nucleus (RTN), a collection of ~2000 glutamatergic neurons in rats that are activated by hypercapnia in vivo and by acidification in slices, had been identified as a CRC candidate just prior to my PhD work. My first objective was to seek additional and critical evidence that RTN neurons are CRCs by determining whether these neurons stimulate breathing in proportion to arterial PCO 2 in intact unanesthetized rats.Having verified that this was the case I tested a logical corollary of this theory namely that RTN is silenced under hypoxic conditions due to respiratory alkalosis. Then I proceeded to test whether RTN neurons sustain breathing automaticity during sleep. Finally, I tested whether RTN compensates for the lack peripheral chemoreceptor input.Methods: RTN neurons were bilaterally transduced to express the proton pump archaerhodopsin using a lentiviral vector. Using anesthetized rats, I confirmed that RTN neurons were silenced by activating archaerhodopsin with green light. I examined the effect of short periods of RTN inhibition (10s) on breathing (plethysmography), EEG and neck EMG in conscious rats in which arterial pH was changed by exposing the animals to various FiO 2 levels alone or with the addition of 3% FiCO 2 or acetazolamide (ACTZ). Rats were studied in different states of vigilance (quiet awake/non-REM/REM). Arterial blood gases (PaO 2 , PaCO 2 ), pHa and HCO 3 were measured under each condition.ii Results: RTN inhibition (bilateral) reduced breathing frequency and amplitude in direct proportion to arterial plasma pH (pHa) below a threshold of 7.53. Above this level, RTN inhibition had no effect suggesting that the nucleus was silent. In normoxia, RTN inhibition reduced breathing equally during non-REM sleep and quiet wake. By contrast RTN inhibition had very little effect on breathing during REM sleep.Conclusions: RTN drives breathing in direct proportion to arterial PCO 2 in intact unaesthetized rats, consistent with the theory that these neurons are CRCs. RTN neurons are silent above pHa 7.5 and increasingly active below this value. RTN regulates breathing automaticity about equally during non-REM sleep and quiet waking, conditions under which the respiratory pattern generator is autorhythmic. By contrast, RTN has a much reduced influence on breathing during Viar for surgery skills, science advice, life advice, wanted/unwanted music advice and so much more. Together, they made a dynamic group of personalities that provided a stimulating and encouraging atmosphere that will never be forgotten....

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“…Other factors that may raise chemosensitivity include reduced cardiac output via reduced carotid arterial blood flow (64) and hypoxemia (via pulmonary congestion). Hypoxemia raises chemosensitivity both acutely and over time (59, 65). …”

Section: Pathophysiological Considerationsmentioning

confidence: 99%