• Daniel A Keir, James Duffin, Philip J Millar, and John S Floras.
• University Health Network and Mount Sinai Hospital Division of Cardiology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
• J. Physiol. (Lond.). 2019 Jul 1; 597 (13): 3281-3296.

Key PointsCentral chemoreceptor stimulation, by hypercapnia (acidosis), and peripheral, by hypoxia plus hypercapnia, evoke reflex increases in ventilation and sympathetic outflow. The assumption that central or peripheral chemoreceptor-mediated sympathetic activation elicited when P C O 2 increases parallels concurrent ventilatory responses is unproven. Applying a modified rebreathing protocol that equilibrates central and peripheral chemoreceptor P C O 2 whilst clamping O2 tension at either hypoxic or hyperoxic concentrations, the independent ventilatory and muscle sympathetic stimulus-response properties of the central and peripheral chemoreflexes were quantified and compared in young men. The novel findings were that ventilatory and sympathetic responses to central and peripheral chemoreflex stimulation are initiated at similar P C O 2 recruitment thresholds but individual specific sympathetic responsiveness cannot be predicted from the ventilatory sensitivities of either chemoreceptor reflex. Such findings in young men, if replicated in heart failure or hypertension, should temper present enthusiasm for trials targeting the peripheral chemoreflex based solely on ventilatory responsiveness to non-specific chemoreceptor stimulation.AbstractIn humans, stimulation of peripheral or central chemoreceptor reflexes is assumed to evoke equivalent ventilatory and sympathetic responses. We evaluated whether central or peripheral chemoreceptor-mediated sympathetic activation elicited by increases in CO2 tension ( P C O 2 ) parallels concurrent ventilatory responses. Twelve healthy young men performed a modified rebreathing protocol designed to equilibrate central and peripheral chemoreceptor P C O 2 tensions with end-tidal P C O 2 ( P ETC O 2 ) at two isoxic end-tidal P O 2 ( P ET O 2 ) such that central responses can be segregated, by hyperoxia, from the net response (hypoxia minus hyperoxia). Ventilation and muscle sympathetic nerve activity (MSNA) were recorded continuously during rebreathing at isoxic P ET O 2 of 150 and 50 mmHg. During rebreathing, the P ETC O 2 values at which ventilation (L min-1 ) and total MSNA (units) began to rise were identified ( P ETC O 2 recruitment thresholds) and their slopes above the recruitment threshold were determined (sensitivity). The central chemoreflex recruitment threshold for ventilation (46 ± 3 mmHg) and MSNA (45 ± 4 mmHg) did not differ (P = 0.55) and slopes were 2.3 ± 0.9 L min-1  mmHg-1 and 2.1 ± 1.5 units mmHg-1 , respectively. The peripheral chemoreflex recruitment thresholds, at 41 ± 3 mmHg for both ventilation and MSNA were lower (P < 0.05) compared to the central chemoreflex recruitment thresholds. Peripheral chemoreflex sensitivity was 1.7 ± 0.1 L min-1  mmHg-1 for ventilation and 2.9 ± 2.6 units mmHg-1 for MSNA. There was no relationship between the ventilatory and MSNA sensitivity for either the central (r2  = 0.01, P = 0.76) or peripheral (r2  = 0.01, P = 0.73) chemoreflex. In healthy young men, ventilatory and sympathetic responses to central and peripheral chemoreceptor reflex stimulation are initiated at similar P ETC O 2 recruitment thresholds but individual ventilatory responsiveness does not predict sympathetic sensitivities of either chemoreflex.© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.

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