Reappraisal of systemic venous chemoreceptors: might they explain the matching of breathing to metabolic rate in humans?

Abstract

What is the topic of this review? One of the major unanswered questions in physiology is that of how breathing matches metabolic rate. Venous chemoreceptors seem to have been dismissed since the 1960s. What advances does it highlight? New evidence shows that their apparent dismissal needs reappraisal. The paper on which this depends has more than one interpretation, and another paper obtained the opposite result. Previous search ignored all locations between skeletal muscle and the right heart. Oxygen sensors other than the arterial chemoreceptors do exist. Heymans and colleagues originally demonstrated some residual breathing response to hypoxia in sino-aortically denervated animals. Similar results occur in humans. One of the major unanswered questions in physiology is that of how breathing matches metabolic rate. The existence in humans of venous chemoreceptors that might control breathing seems to have been dismissed since the 1960s. New evidence has emerged showing that this apparent dismissal needs reappraisal. First, the paper in humans on which this depends has more than one interpretation. Moreover, a previous paper obtained the opposite result and is not cited. Secondly, previous search for venous chemoreceptors failed to examine all venous locations between skeletal muscle and the right heart and lungs. Thirdly, oxygen sensors other than the arterial chemoreceptors do exist. Heymans himself originally demonstrated some residual breathing response to hypoxia in sino-aortically denervated animals. Others confirm a residual breathing response to hypoxia in mammals, including humans. There is now considerable interest in the importance of afferent feedback in controlling the cardiovascular and respiratory systems. Moreover, it is now clear that arterial, aortic and central chemoreceptors have no role in explaining how breathing matches metabolic rate during exercise. These together provide a timely reminder that venous chemoreceptors remain ideal candidates still to be considered as metabolic rate sensors to explain matching in humans. Firstly, this is because venous PO2 and PCO2 values do change appropriately in proportion to metabolic rate, so a metabolic rate signal sufficient to drive breathing might already exist. Secondly, chemoreceptor-like anatomical structures are present in the systemic venous system but remain unexplored. Finally, no extant experimental evidence precludes their existence.

Respiratory anomalies associated with gadoxetate disodium and gadoterate meglumine: compressed sensing MRI revealing physiologic phenomena during the entire injection cycle

“…Conversely, pulmonary or venous trigger locations could be the cause. Yet, the impact and precise mechanism of peripheral venous chemoreceptors is still a field of ongoing investigation [ 15 ]. Of importance, however, is the fact that not a single transient respiratory motion event was detected prior to the presence of gadolinium-containing contrast material in the vascular system.…”

Control of exercise hyperpnoea: Contributions from thin‐fibre skeletal muscle afferents

“…As stated above, however, /H + (and ) changes little during exercise, and although P CO 2 increases proportionately with workload (Figure b), there is currently no strong anatomical or functional evidence supporting the existence of chemoreceptors in the venous circulation that can drive the exercise hyperpnoea (although their existence is still be possible; for review, see Parkes, ). Despite this, other mechanisms have been hypothesized, which might permit arterial chemoreceptors to contribute to the exercise ventilatory response, such as an increased chemosensitivity to .…”

“…Respiratory control neurones in the brainstem receive both excitatory and inhibitory inputs from several sources, including skeletal muscle metaboreceptive and mechanoreceptive afferents, central command, and feedback from central and peripheral chemoreceptors and from lung/airway mechanoreceptors; these inputs are hypothesized to contribute to the normal ventilatory responses to exercise. The existence/involvement of venous chemoreceptors (top left), which would monitor blood within the right heart and/or pulmonary circulation, is still debated(Parkes, 2017). Abbreviations are as in Figure1.…”

Physiological Function during Exercise and Environmental Stress in Humans—An Integrative View of Body Systems and Homeostasis

“…How pulmonary VE is regulated during exercise is only partly understood and subject to much controversy [126][127][128]. Beyond humoral (blood-borne) factors, which can stimulate ventilation via activation of central (medullary neurons) and peripheral (carotid bodies) chemoreceptors, ventilatory changes during exercise seem heavily reliant on fastacting neural feed-forward (i.e., an augmented central command [129]) and feedback from mechano-and metaboreceptors (particularly from locomotor muscle group III and IV afferents [130,131]).…”