ReviewAn interdependent model of central/peripheral chemoreception: Evidence and implications for ventilatory control☆
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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This paper is part of a special issue entitled “Central Chemoreception”, guest-edited by “Drs. E.E. Nattie and H.V. Forster”.