Theories on the nature of the coupling between ventilation and gas exchange during exercise

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Abstract

For over a century of creative research, many theories on the possible mechanisms controlling respiration during exercise have been developed and discussed. One of the most enduring questions is certainly related to the mechanisms that can prevent PaCO2 rising when CO2 production increases.

As multiple systems and structures are capable of increasing ventilation (V˙E), not all the mechanisms controlling respiration can provide a proper answer to this question. Indeed, exercise is a complex physiological condition combining motor activity with a change in metabolic rate. The most intriguing aspect of exercise is that when the changes in metabolism are dissociated from the motor and locomotor activity, the strategy ‘chosen’ by the respiratory control system is to follow the metabolic rate (or more precisely factors temporally associated with the pulmonary gas exchange rate) regardless of the motor act. The strategy used by the respiratory system during exercise therefore appears to select from among various sources of information the most relevant to follow the rate at which CO2 is ultimately exchanged by the lungs. Yet, the nature of the signal(s) which prevents CO2/H+ disturbance during exercise is the fundamental question addressed by this simple observation and remains to be clarified.

This review illustrates the attempts of many physiologists to collect experimental evidence for theories which could provide satisfactory mechanisms accounting for the matching between ventilation and the rate at which CO2 leaves the tissues and is exchanged at the lungs. More recent models based on somatic information of circulatory origin are presented and discussed.

Introduction

One of the most challenging questions in respiratory physiology is certainly that of the mechanisms of arterial PCO2/pH control during muscular dynamic exercise (Krogh and Lindhard, 1913, Grodins, 1950, Kao, 1956, Dejours et al., 1957a, Dejours, 1963). When the metabolic – and thus the pulmonary gas exchange – rate increases as a result of muscular activity, ventilation appears to rise in proportion and prevents hypercapnia (and hypoxia) from occurring (Whipp and Ward, 1991, Whipp and Ward, 1998).

Extensive and numerous reviews have been written on this subject (Dejours, 1959, Wasserman et al., 1979, Dempsey et al., 1984, Eldridge and Waldrop, 1991, Whipp and Ward, 1991), and the search for the mechanisms coupling ventilatory control to factors proportional or related to the gas exchange rate has triggered, for many decades, creative and fascinating debates. The discussion on this subject is still very vivid, not only because it is one of the most controversial, and as of yet unanswered, questions in physiological regulation but also because many types of patients suffering from dyspnea on exertion would benefit from a better understanding of the structures involved in the V˙E–metabolism coupling.

The literature in this domain is so vast that one may find published studies which support a given concept and an equal number of experiments apparently supporting just the opposite. This may cause perplexity to many readers. Besides, the control of exercise hyperpnea covers very different domains of research with their specific techniques and language, from fundamental neurophysiology to mathematical analysis of the responses in exercising humans. The fact that studies published in one given domain are at odds with the results obtained in another field is often ignored simply because they belong to a different area of research. For instance, whether a concept imagined from a reduced preparation is compatible with the simple description of the dynamic of the ventilatory response to exercise in humans should be systematically tested. Finally, the primary control systems could be affected by “external” factors with long lasting effects, a phenomenon which has been overlooked (see Mitchell and Johnson, 2003 for discussion) and which makes the study of such control mechanisms more complicated. This implies that observation in “intact” animals and in humans should dictate the direction taken by the most fundamental research and not the opposite.

This short review will focus primarily on the possible sites of mediation between gas exchange and ventilation. First, we will try to explain the reasons why so many physiologists have believed (and still believe) that there is a ventilatory–metabolism coupling, independent of the motor component of exercise. We will illustrate that when the work load or the frequency of movements are dissociated from the gas exchange rate, ventilation follows factors related or proportional to the changes in gas exchange and not to the motor act, regardless of the magnitude of the centrally or peripherally mediated signal related to the locomotion. Secondly, we will examine the most important attempts to understand the nature of such a coupling in exercise. Finally, we will try to discuss whether new ideas have emerged to answer this question.

Section snippets

Is ventilation linked to factors related to motor and locomotor activity or to gas exchange during dynamic exercise?

Dynamic exercise is a complex situation which combines an increase in metabolic rate and a motor act. The increase in metabolic rate certainly changes the local chemical environment of the muscle, the composition of the venous blood and the rate of change in alveolar gas composition through the respiratory cycle, and is associated with systemic and local circulatory responses (increase in blood flow).

The motor act requires the voluntary and automatic control of movements and produces

Kao's experiments

Kao (1963) and Kao et al. (1963) probably contributed the most impressive series of observations on the role of somatic information during exercise as fundamental factors for PaCO2 homeostasis in animal preparations. In a sophisticated series of experiments, he studied the V˙E response in dogs in which the circulatory systems were connected in such a way that the blood leaving the exercising muscles of one dog (the neural dog) was infused into the venous system of another animal (the humoral

Conclusions

Studies attempting to dissociate in the frequency domain factors related to the motor act from those related to the gas exchange have shown that the main part of the V˙E response to exercise follows the latter (Casaburi et al., 1978). This approach has revealed a fundamental property of the respiratory control system during exercise, i.e. that not all the inputs to the respiratory neurons are taken into account. The strategy adopted by the respiratory control system is to follow factors related

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