The ventilatory and sympathetic responses to central and peripheral chemoreflex stimulation in disease states: the other side of the same coin

Abstract

Breathing relies on a complex neural network in the brainstem that controls respiratory rhythm and pattern generation, which is continually modulated by specific central and peripheral chemoreflexes that maintain blood gas homeostasis in the body. Central chemoreceptors located in many brainstem areas, including the nucleus tractus solitarii (NTS), raphe nuclei, locus coeruleus, pre-Bötzinger complex and the retro trapezoid nucleus, sense local changes in tissue [H+] to drive ventilation. On the other hand, in response to reduced arterial oxygen tension, input from oxygen-sensing type I glomus cells in the carotid body (peripheral chemoreceptors) reaches medullary cardiorespiratory centres through the glossopharyngeal nerve, exciting neurons in the NTS that provoke hyperventilation, tachycardia and increased sympathetic outflow to the heart and blood vessels to maintain or re-establish tissue PO2 . These peripheral chemoreceptors also sense changes in the chemical composition of the blood (e.g. carbon dioxide (CO2), hydrogen ions (H+), lactate, potassium, glucose, insulin and angiotensin) and despite the existence of different chemosensitive areas, the central and peripheral chemoreflex systems operate synergically via a powerful negative feedback loop, maintaining arterial PCO2 (PaCO2 ) within very narrow limits (Zera et al. 2019). However, whether central and peripheral chemoreceptor-evoked sympathetic and ventilatory discharge exhibit different recruitment thresholds and sensitivity is not fully understood. In a recent issue of The Journal of Physiology, Keir and colleagues (2019) eloquently enlarged the body of knowledge about the independent contributions of the central and peripheral chemoreflexes to the integrated ventilatory and sympathetic response to changes in PaCO2 in humans. To address this concern, three hypotheses were tested: whether muscle sympathetic nerve activity (MSNA) responses to selective central or peripheral chemoreceptor stimulation would be characterized; whether the elicited ventilatory and MSNA responses increase in parallel; and whether end-tidal PCO2 (PETCO2 ) thresholds and sensitivities for ventilatory and MSNA responses to central and peripheral chemoreflex stimulation would be similar within subjects. To test these hypotheses, the authors simultaneously quantified ventilatory and MSNA responses at rest and during a Duffin modified rebreathing procedure. Briefly, this method entails measurement of the ventilatory and sympathetic responses to CO2 in subjects rebreathing from a bag of known PCO2 and PO2 . Each test consisted of a baseline phase where the subjects breathed room air, a hyperventilation phase where the subjects hyperventilated to a target PETCO2 25 mmHg for 3 min, followed by dynamic rebreathing. During rebreathing, there is an equilibration of PCO2 within the bag, exhaled gas, lungs and arterial and venous blood, allowing an accumulation of CO2, which gradually increases the PCO2 of the entire system. Dynamic rebreathing consisted of subjects rebreathing a bag which initially held O2 at a PO2 of 150 mmHg (hyperoxic test) and 30 mmHg (hypoxic test), and CO2 at a PCO2 of 42 mmHg. In order to explore chemoreflex sensitivity, silencing of hypoxia-related input from the peripheral chemoreceptors by hyperoxic rebreathing gas enables the assessment of the central chemoreflex contribution. Thus, the difference between the hypoxic and hyperoxic rebreathing tests reflects the specific peripheral chemoreflex contribution to the net response. The main finding of Keir et al. (2019) was that the PETCO2 evoked an MSNA and ventilatory response at the same threshold. However, during the isoxic hyperoxic condition (which estimates the central chemoreflex) PETCO2 evoked ventilatory and MSNA responses at a higher PETCO2 threshold (45.6 ± 3.3 mmHg vs. 45.0 ± 4.2 mmHg, respectively), whereas the evoked ventilatory and MSNA responses occur at a lower PETCO2 threshold (41.2 ± 3.1 mmHg vs. 41.4 ± 3.2 mmHg, respectively) for the estimated peripheral chemoreceptors (hypoxic minus hyperoxic rebreathing tests). The ventilatory and MSNA central chemoreflex sensitivities were 2.3 ± 0.9 l min−1 mmHg−1 and 2.1 ± 1.5 a.u. mmHg−1, respectively, and the estimated peripheral chemoreflex sensitivities were 1.7 ± 0.1 l min−1 mmHg−1 and 2.9 ± 2.6 a.u. mmHg−1, respectively (where a.u. represents arbitrary units). Despite the similar thresholds, the authors did not find a relationship between ventilatory and MSNA sensitivities, which means that the sympathetic responsiveness cannot be explained by the ventilatory sensitivities independent of the central and peripheral chemoreflexes. From a clinical perspective, in the study of Keir et al. (2019) most attention focuses on conditions characterized by an exaggerated activation of the sympathetic nervous system, while much less is given to circumstances that present evidence of sympathetic hypoactivity. It is known that pathologies such as hypertension have been related to an increased sympathetic activity in the resting condition but also to exaggerated sympathoexcitation to peripheral chemoreflex activation (Fernandes et al. 2018). From the other side of the coin, however, there is a growing interest in neurological disorders that have been related to conditions of sympathetic hypoactivity. Recent studies have suggested that the attenuated chemoreflex response plays an important role in the respiratory dysfunction of patients with Parkinsons’s disease (PD) rather than impairment of the ventilatory muscle function. For example, Serebrovskaya et al. (1998) reported that male patients with PD under Sinemet-250 medication (to avoid any peripheral dopamine influence) presented a reduced ventilatory response during severe isocapnic hypoxia. Of note, the patients presented normal voluntary hyperventilation, suggesting that the motor impairment of