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INVITED REVIEW

EXERCISE AND RESPIRATORY PHYSIOLOGY

Integration of cerebrovascular CO₂ reactivity and chemoreflex control of breathing: mechanisms of regulation, measurement, and interpretation

¹Department of Physiology, University of Otago, Dunedin, New Zealand; ²Department of Human Kinetics, Faculty of Health and Social Development, University of British Columbia, Okanagan, Kelowna, Canada; and ³Departments of Anaesthesia and Physiology, University of Toronto, Toronto, Ontario, Canada

Cerebral blood flow (CBF) and its distribution are highly sensitive to changes in the partial pressure of arterial CO₂ (Pa_CO2). This physiological response, termed cerebrovascular CO₂ reactivity, is a vital homeostatic function that helps regulate and maintain central pH and, therefore, affects the respiratory central chemoreceptor stimulus. CBF increases with hypercapnia to wash out CO₂ from brain tissue, thereby attenuating the rise in central PCO₂, whereas hypocapnia causes cerebral vasoconstriction, which reduces CBF and attenuates the fall of brain tissue PCO₂. Cerebrovascular reactivity and ventilatory response to Pa_CO2 are therefore tightly linked, so that the regulation of CBF has an important role in stabilizing breathing during fluctuating levels of chemical stimuli. Indeed, recent reports indicate that cerebrovascular responsiveness to CO₂, primarily via its effects at the level of the central chemoreceptors, is an important determinant of eupneic and hypercapnic ventilatory responsiveness in otherwise healthy humans during wakefulness, sleep, and exercise and at high altitude. In particular, reductions in cerebrovascular responsiveness to CO₂ that provoke an increase in the gain of the chemoreflex control of breathing may underpin breathing instability during central sleep apnea in patients with congestive heart failure and on ascent to high altitude. In this review, we summarize the major factors that regulate CBF to emphasize the integrated mechanisms, in addition to Pa_CO2, that control CBF. We discuss in detail the assessment and interpretation of cerebrovascular reactivity to CO₂. Next, we provide a detailed update on the integration of the role of cerebrovascular CO₂ reactivity and CBF in regulation of chemoreflex control of breathing in health and disease. Finally, we describe the use of a newly developed steady-state modeling approach to examine the effects of changes in CBF on the chemoreflex control of breathing and suggest avenues for future research.

cerebral blood flow; ventilation; reactivity

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