An interdependent model of central/peripheral chemoreception: Evidence and implications for ventilatory control

doi:10.1016/j.resp.2010.02.015

Respiratory Physiology & Neurobiology

Volume 173, Issue 3, 31 October 2010, Pages 288-297

https://doi.org/10.1016/j.resp.2010.02.015 Get rights and content

Abstract

In this review we discuss the implications for ventilatory control of newer evidence suggesting that central and peripheral chemoreceptors are not functionally separate but rather that they are dependent upon one another such that the sensitivity of the medullary chemoreceptors is critically determined by input from the carotid body chemoreceptors and vice versa i.e., they are interdependent. We examine potential interactions of the interdependent central and carotid body (CB) chemoreceptors with other ventilatory-related inputs such as central hypoxia, lung stretch, and exercise. The limitations of current approaches addressing this question are discussed and future studies are suggested.

Introduction

Traditionally, since the time of Heymans and Comroe, a key area of interest in the control of breathing has been the relative influence of peripheral vs. medullary chemoreceptors in the ventilatory response to hypercapnia, hypocapnia, and hypoxia. The peripheral and central chemoreceptors were usually viewed as independent entities responding solely to the [H⁺], PCO₂ and PO₂ in their environments, their outputs being summated in a fixed way (Fig. 1). In this review we discuss the implications of newer evidence suggesting that these two sets of receptors are not functionally separate but rather that they are dependent upon one another such that the sensitivity of the medullary chemoreceptors is critically determined by input from the peripheral chemoreceptors and possibly other breathing-related reflex afferents as well i.e., they are interdependent. There is also evidence showing the converse i.e., the degree of central stimulation can affect the sensitivity of the peripheral chemoreceptors.

Section snippets

Models of central/peripheral interdependence

Since the late 1960s the region of the ventrolateral medulla termed “area S” or “intermediate area” has been suspected of having integrative properties at least for chemoafferent and airway rapidly adapting receptor signals involved in the control of breathing (Schlaefke and Loeschcke, 1967, Cherniack et al., 1979, Millhorn and Kiley, 1984, Millhorn and Eldridge, 1986). Within the past decade more direct neuroanatomical and neurophysiological evidence from reduced preparations has given rise to

The nature of interdependence is controversial

The concept of interaction between central and peripheral chemoreceptors (as opposed to the well-known CO₂/hypoxia interaction at the carotid body chemoreceptors) remains controversial. Although known for many years, it has perhaps not been widely appreciated that any interaction other than simple additive interaction (i.e., no change in slope of the ventilatory response) requires some sort of modulation of one set of receptors by the other (e.g., Adams and Severns, 1982). Thus, hypoadditive

Implications for the “Relative Contribution” concept

How does the concept of interdependent chemoreceptors fit with the “60:40”contribution generally presumed for central:peripheral chemoreceptor contributions to the whole body CO₂ response? The effects of bilateral carotid body denervation in unanesthetized animals have been used to partition the ventilatory response to CO₂ to about a 60:40 central/peripheral split (Kiwull et al., 1972, Bisgard et al., 1976, Pan et al., 1998, Rodman et al., 2001). A hyperoxic background to the inspired CO₂—using

Implications for eupnea

Interdependence of peripheral and central chemoreceptors would suggest an important role for carotid body chemoreceptors even during quiet eupnea and some recent data supports this idea. Blain et al. (2009) used an unanesthetized canine model with reversibly isolated carotid bodies that were perfused from an extracorporeal gas exchanger that allowed control of the blood gas environment of the carotid bodies independently of the systemic (and, importantly, brain) circulation. They inhibited the

Implications for sleep-induced periodic breathing and apnea

With the loss of wakefulness at the onset of non-REM sleep the control of breathing becomes exquisitely dependent upon chemoreceptor influences especially on PCO₂. Apneas due to loss of central respiratory motor output commonly occur following a brief ventilatory overshoot and transient hypocapnia. Controlled studies using progressive levels of mechanical ventilation to mimic the transient ventilatory overshoot have demonstrated that the apneic threshold for PaCO₂ in healthy sleeping subjects

Acute hypoxia

Based largely on studies in anesthetized preparations that had been carotid body denervated, made hypoxic with carbon monoxide (Neubauer et al., 1985, Melton et al., 1988, Melton et al., 1992), or exposed to specific pontomedullary hypoxia (van Beek et al., 1984), it was long thought that the direct effect of hypoxia on the CNS was ventilatory depression. However, when unanesthetized carotid body denervated animals were made hypoxic most studies reported that ventilation was unchanged or

Role of chemoreceptors and chemoreceptor interactions in exercise hyperpnea

The ventilatory response to exercise is proportional to the increasing metabolic requirement in mild to moderate exercise and rises out of proportion to metabolism in heavy exercise. The dominant mechanism for this ventilatory response remains unknown, but two locomotor-related mechanisms are clearly involved, namely: (a) the feedforward link of a descending drive to the spinal motor neurons driving locomotion that originate in locomotor regions of the hypothalamus and cerebellum and which

Does the type of carotid body stimulus affect central/peripheral interaction?

Does the type of carotid body stimulus determine the observed interaction between carotid body chemoreceptors and central chemoreceptors? In other words, is the central/peripheral interaction always the same for a given amount of carotid sinus nerve afferent traffic or does the nature of the carotid body stimulus affect the outcome? There is a paucity of data on this topic; nevertheless there are hints that the nature of the carotid body stimulus may affect central responses and therefore

Future directions

The neuroanatomical and neurophysiological evidence in favor of an integrative function for the RTN, probably in conjunction with other neural loci (e.g., NTS, pons (Kubin et al., 2006, Kline, 2008)) seems compelling but we believe that the physiological significance of these pathways has not yet been established. Most of the experiments on this topic were performed in highly reduced, anesthetized preparations. In addition to the anesthesia, procedures such as decerebration, carotid body

Acknowledgments

Work cited from our laboratories was supported by grants from the National Heart Lung and Blood Institute of the National Institutes of Health (Smith, Dempsey, Blain: HL 50531, HL 15469; Forster: HL 25739); the American Heart Association (Smith, Dempsey, Blain) and the Department of Veterans Affairs (Forster).

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Effective cough requires a significant increase in lung volume used to produce the shear forces on the airway to clear aspirated material. This increase in tidal volume during cough, along with an increase in tidal frequency during bouts of paroxysmal cough produces profound hyperventilation and thus reduces arterial CO₂. While there are several reports in the literature regarding the effects of hypercapnia, hyperoxia, and hypoxia on cough, there is little research quantifying the effects of hypocapnia on the cough reflex. We hypothesized that decreased CO₂ would enhance coughing. In 12 spontaneously breathing adult male cats, we compared bouts of prolonged mechanically stimulated cough, in which cough induced hyperventilation (CHV) was allowed to occur, with isocapnic cough trials where we maintained eupneic end-tidal CO₂ by adding CO₂ to the inspired gas. Isocapnia slightly increased cough number and decreased esophageal pressures with no change in EMG magnitudes or phase durations. The cough-to-eupnea transition was also analyzed between CHV, isocapnia, and a third group of animals that were mechanically hyperventilated to apnea. The transition to eupnea was highly sensitive to added CO₂, and CHV apneas were much shorter than those produced by mechanical hyperventilation. We suggest that the cough pattern generator is relatively insensitive to CHV. In the immediate post-cough period, the appearance of breathing while CO₂ is very low suggests a transient reduction in apneic threshold following a paroxysmal cough bout.
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Citation Excerpt :
Looking at nocturnal breathing patterns at HA, there is a general agreement on the role played by several mechanisms during high altitude exposure, among which hypoxia-induced hyperventilation, low PaCO2 and greater chemoreflex sensitivity, which lead to an instability in the ventilatory control system, must be mentioned [29]. Central apneas occur when arterial pCO2 falls below the threshold required to stimulate breathing, while hyperpnea occurs with reduced arterial pO2 [30]. A previous study by Latshang et al. showed the occurrence of periodic breathing even at MA in healthy, very young males [15].
Acute exposure to high altitude (>2500 m) is known to induce a rise in blood pressure (BP) and the appearance of sleep related breathing alterations, in particular central sleep apneas and periodic breathing. Little information is available on whether this is the case in humans also for acute exposure to moderate altitude (between 1500 and 2500 m). Aim of this study was to evaluate the effects of acute exposure of healthy volunteers to moderate altitude on conventional and ambulatory BP as well as on the frequency and severity of breathing alterations during sleep.
Forty-four healthy lowlanders underwent 24-hour ambulatory BP monitoring and nocturnal cardio-respiratory sleep study at sea level and during acute (1–2 days after arrival) exposure to moderate altitude (2035 m, Sestriere, Italy). The key variables investigated included average systolic and diastolic BP and heart rate over daytime, night-time and 24 h, the frequency of obstructive and central apneas/hypopnoeas and the behaviour of oxygen saturation during sleep.
Compared to sea level, during moderate altitude exposure mean systolic/diastolic BP increased significantly during daytime (respectively from 125.6 ± 10.9 to 130.6 ± 12.3, p = 0.0032 and from 78.8 ± 6.7 to 81.8 ± 7.7 mmHg, p = 0.0048) and during night-time (respectively from 102.4 ± 12.4 to 107.4 ± 12.7, p = 0.0028, and from 62.0 ± 8.2 to 65.8 ± 8.2 mmHg, p = 0.0014), with no change in nocturnal BP dipping. BP increase was more evident in participants aged over 40 years. Apnea-hypopnea index (AHI) increased from 1.60 (0.40–2.90) to 5.4 (2.90–10.60), p < 0.0001), mainly because of increasing frequency of hypopneas and central apneas, in particular in males aged over 40 years. No association was found between size of BP changes and AHI.
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^☆: This paper is part of a special issue entitled “Central Chemoreception”, guest-edited by “Drs. E.E. Nattie and H.V. Forster”.

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ReviewAn interdependent model of central/peripheral chemoreception: Evidence and implications for ventilatory control☆

Abstract

Introduction

Section snippets

Models of central/peripheral interdependence

The nature of interdependence is controversial

Implications for the “Relative Contribution” concept

Implications for eupnea

Implications for sleep-induced periodic breathing and apnea

Acute hypoxia

Role of chemoreceptors and chemoreceptor interactions in exercise hyperpnea

Does the type of carotid body stimulus affect central/peripheral interaction?

Future directions

Acknowledgments

Respir. Physiol.

Respir. Physiol.

Respir. Physiol.

Respir. Physiol.

Respir. Physiol.

Respir. Physiol.

Respir. Physiol.

Respir. Physiol.

Respir. Physiol.

Respir. Physiol.

Respir. Physiol.

Respir. Physiol.

Respir. Physiol.

Respir. Physiol.

Chest

Respir. Physiol. Neurobiol.

Respir. Physiol.

Respir. Physiol.

Respir. Physiol.

Respir. Physiol.

Respir. Physiol.

J. Ultrastruct. Res.

Medullary and carotid chemoreceptor interaction for mild stimuli

Pflugers Arch.

Interaction of chemoreceptor effects and its dependence on the intensity of stimuli

J. Appl. Physiol.

Ventilatory responses to CO2 during work at normal and at low oxygen tensions

Acta Physiol. Scand.

Determinants of poststimulus potentiation in humans during NREM sleep

J. Appl. Physiol.

Pharyngeal narrowing/occlusion during central sleep apnea

J. Appl. Physiol.

Interaction between chemoreceptor and stretch receptor inputs at medullary respiratory neurons

Am. J. Physiol.

Time-dependent effect of hypoxia on carotid body chemosensory function

J. Appl. Physiol.

Interaction of peripheral and central respiratory drives in cats. I. Effects of sodium cyanide as a peripheral chemoreceptor stimulus at different levels of CSF pH

Pflugers Arch.

Mechanisms of hypoxia-induced periodic breathing during sleep in humans

J. Physiol. (Lond.)

Ventilatory acclimatization to hypoxia is not dependent on cerebral hypocapnic alkalosis

J. Appl. Physiol.

Hypoventilation in ponies after carotid body denervation

J. Appl. Physiol.

Contribution of the carotid body chemoreceptors to eupneic ventilation in the intact, unanesthetized dog

J. Appl. Physiol.

Ventilatory acclimatization and csf acid–base balance in carotid chemodenervated dogs at 3550 m

Pflugers Arch.

Effect of carotid body denervation on arousal response to hypoxia in sleeping dogs

J. Appl. Physiol.

Ventilatory acclimatization to hypoxia is not dependent on arterial hypoxemia

J. Appl. Physiol.

Second messenger regulation of tyrosine hydroxylase gene expression in rat carotid body

Biol. Signals

Role of endothelin and endothelin A-type receptor in adaptation of the carotid body to chronic hypoxia

Am. J. Physiol. Lung Cell Mol. Physiol.

Respiratory adaptations to chronic high altitude hypoxia

J. Appl. Physiol.

An assessment of central–peripheral ventilatory chemoreflex interaction using acid and bicarbonate infusions in humans

J. Physiol. (Lond.)

Ventilatory responses to specific CNS hypoxia in sleeping dogs

J. Appl. Physiol.

Phox2b controls the development of peripheral chemoreceptors and afferent visceral pathways

Development

The respiratory responses to anoxemia of unanesthetized dogs with chronically denervated aortic and carotid chemoreceptors and their causes

Am. J. Physiol.

Review
An interdependent model of central/peripheral chemoreception: Evidence and implications for ventilatory control☆

Ventilatory responses to CO₂ during work at normal and at low oxygen tensions

Brainstem PCO₂ modulates phrenic responses to specific carotid body hypoxia in an in situ dual perfused rat preparation

Role of cerebrospinal fluid [H⁺] in ventilatory deacclimatization from chronic hypoxia