Central CO2 chemoreception in cardiorespiratory control.

HYPERCAPNIA, largely through the direct influence of CO2 on proton production, but possibly also via a direct effect of molecular CO2, is the primary chemical stimulus for alveolar ventilation. Small deviations in arterial CO2 in either direction elicit integrated cardiorespiratory reflexes that quickly restore CO2 levels in various tissue and cellular compartments, thereby providing the body with its most rapid physiological mechanism for pH regulation and homeostasis. A reduction in arterial oxygenation under normocapnic conditions, by contrast, does not stimulate alveolar ventilation significantly until it drops below 60 Torr and begins endangering oxygen uptake by hemoglobin in the pulmonary circulation. Thus understanding how CO2 and pH levels are monitored in the body and regulated provides insight to the fundamental control mechanism that sets alveolar ventilation and pH homeostasis during wakefulness and sleep. Congenital and adult-onset abnormalities of the CO2 chemoreceptors are thought to contribute to onset of disordered breathing patterns and various chronic central hypoventilation syndromes that lead to chronic acidbase imbalance, redox stress, and nitrosative stress that produce additional neurological deficits. The peripheral CO2 chemoreceptors that monitor the partial pressure of CO2 (PCO2) and pH in plasma are located unequivocally within the carotid bodies. The anatomical isolation of these small but well vascularized and perfused structures lends them to easy visualization and experimental manipulation while simultaneously measuring ventilation to confirm their function in CO2/H chemoreception. The intracranial chemoreceptors, by contrast, which are the focus of this Highlighted Topic series, are more difficult to isolate, and the extent of their distribution in the brain stem is still being debated (1, 10, 16, 18). The first intracranial chemoreceptor area was identified in 1963 by Mitchell and colleagues (13) on the ventrolateral medullary (VLM) surface. They proposed that this was the sole site of CO2 chemoreception in the brain stem, a theory that would be embraced by nearly all cardiorespiratory neurophysiologists for the next two decades. In 1983, Miles (12) and later, others (3, 5), challenged this idea and suggested that neurons in the caudodorsal medulla in the vicinity of the nucleus tractus solitarius (NTS) also functioned in CO2/H chemoreception. Over the next two decades, several independent laboratories using a variety of in vivo and in vitro methodologies reported that CO2 chemosensitivity was distributed across additional brain stem nuclei, including the locus ceruleus (LC), medullary raphe (MR), retrotrapezoid nucleus (RTN), rostroventrolateral medulla (RVLM), pre-Bötzinger complex (PBC), and cerebellar fastigial nucleus. In recent years, the VLM surface theory has been “resurrected” with particular importance assigned to the RTN (8). This has reignited the debate as to which region(s) of the CNS is/are the principal sites of intracranial CO2 chemoreception. This ongoing debate has reinvigorated the field and, in the process, provided the rationale for this Highlighted Topic series on “Central CO2 Chemoreception in Cardiorespiratory Control.” While the series does not focus on the debate of central CO2 chemoreceptor location per se, it does address it to a certain extent by including summaries of studies done at multiple chemosensitive areas for the readers’ consideration. The primary topics covered can be roughly categorized as follows: cellular mechanisms of chemoreceptor signaling and the role of pH and other stimuli (4, 6, 11, 14, 17); mechanisms of neural integration of central chemoreceptors with peripheral chemoreceptor afferents and cardiovascular circuits (7, 9); factors and conditions that modulate central chemoreceptor activity (4, 15); and the contribution of central chemoreceptor dysfunction to central hypoventilation syndromes (2). The first review “Contributions of central and peripheral chemoreceptors to the ventilatory response to CO2/H ” (7) summarizes the evidence from studies using anesthetized, decerebrate, and awake animals that addresses the issue of whether the integrated neural signal to breathe produced by carotid and intracranial chemoreceptors during hypercapnic acidosis is additive, hyperadditive, or hypoadditive. The authors conclude that chemosensitivity of the central chemoreceptors is “critically dependent” on input from the peripheral chemoreceptors and that the majority of the evidence supports the notion of hypoadditive interactions. The second review, “Central CO2-chemoreception and integrated neural mechanisms of cardiovascular and respiratory control” (9), addresses the fundamental question of why blood pressure and sympathetic nerve activity increases during stimulation of central CO2 chemoreceptors. Two fundamental mechanisms of integration are postulated for future testing: one that involves central chemoreceptor stimulation of the central pattern generator and results in respiratory modulation of sympathetic nerve activity in the caudal ventrolateral medulla (CVLM), RVLM, NTS, and spinal cord and another that occurs independently of the central pattern generator and is dependent on the relative level of hypercapnia. Under normocapnic conditions, PCO2-dependent activation of chemoreceptors in RTN activate a central sympathetic chemoreflex via RVLM and CVLM neurons, whereas under abnormal hypercapnic conditions, arousal is triggered by activation of wake-promoting Address for reprint requests and other correspondence: J. B. Dean, Dept. of Mol. Pharm. & Physiol., 12901 Bruce B. Downs Blvd., College of Medicine, MDC 8, Univ. of South Florida, Tampa, FL 33612 (e-mail: jdean@health. usf.edu). J Appl Physiol 108: 976–978, 2010; doi:10.1152/japplphysiol.00133.2010. Editorial