INVITED EDITORIAL
Invited Editorial on "Importance of the lactate anion in control of breathing"

Department of Physiology, University of Arizona College of Medicine, Tucson, Arizona 85721-0093

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DURING A PROGRESSIVE-INTENSITY EXERCISE TEST, minute ventilation rises linearly as a function of the exercise power output until the point where lactate begins to accumulate in the plasma. At this point, referred to as the lactate or ventilatory threshold, an inflection point is often evident, and further increases in ventilation are exponential with respect to power output (10). At work rates above the ventilatory threshold, the rate of change of ventilation is more than proportional to the rate of change of CO₂ production (CO₂), and arterial CO₂ partial pressure (Pa_CO2) falls (hyperventilation). The Henderson-Hasselbach equation can be used to show that the fall in Pa_CO2 attenuates the reduction in pH. Thus the hyperventilation is a homeostatic response that partially corrects the metabolic acidosis of heavy exercise.

The stimulus responsible for the hyperventilation of heavy exercise is unknown but has been the subject of considerable study and debate. Much of the attention has been focused on the role of hydrogen ions, as it is well known that this cation stimulates chemosensitive afferents in the carotid body, leading to an increase in ventilation (1). In contrast, the role of the lactate anion has been ignored. The study by Hardarson and colleagues (4) in this issue of the Journal was designed to determine whether the lactate anion itself can increase ventilation in anesthetized rats. They infused a mixture of lactic acid and sodium lactate at pH 4.0, such that the alkalinizing effect of lactate oxidation was neutralized by the acidifying effect of the added acid. They were able to select infusion rates that resulted in progressive increases in plasma lactate concentrations, achieving values up to 20 mM without significant changes in arterial pH. The major finding was that ventilation increased progressively as the lactate levels rose, with no significant change in Pa_CO2. Thus the hyperpnea was isocapnic, implying that CO₂ increased in proportion to the increase in ventilation. The interpretation of these findings is that the metabolism of lactic acid increased CO₂, which then evoked the increase in ventilation. Although an independent effect of the lactate anion cannot be ruled out, there is no evidence for this. Accordingly, this editorial will focus on the link between lactate oxidation, CO₂, and hyperventilation, which is the hypothesis favored by Hardarson and colleagues.

The suggestion that oxidation of lactic acid and the subsequent rise in CO₂ can evoke a reflex increase in ventilation is intriguing because changes in ventilation are highly correlated with changes in CO₂ during exercise. In an effort to examine the mechanism that underlies this association, most effort has been expended searching for three types of sensory feedback (10): 1) CO₂-sensitive afferents in the pulmonary circulation that could sense "CO₂ flow" to the lungs (the product of CO₂ and cardiac output); 2) stretch-sensitive afferents in the lungs that are also CO₂ sensitive; 3) carotid body sensing of arterial CO₂ oscillations. Convincing evidence for either of the first two mechanisms in mammals, including humans, has not been forthcoming (10). Studies designed to evaluate the third mechanism are also inconclusive, but some intriguing results have emerged. The idea, first proposed by Yamomoto and Edwards (11), is that the increase in CO₂ flow to the lungs widens the difference between inspired and expired Pa_CO2, and the enhanced amplitude and frequency of the oscillations are sensed by chemosensitive cells in the carotid body, leading to increased respiratory drive. However, the evidence for carotid body sensing of CO₂ oscillations, although interesting, is circumstantial. For example, Cross and colleagues (2) have shown that exercise enhances CO₂ oscillations in the arterial blood of exercising dogs and suggested that this observation may have provided a signal for the exercise hyperpnea. Phillipson et al. (9) showed that ventilation and CO₂ flow to the lungs were very tightly coupled in awake sheep, whether the changes in CO₂ flow were induced by exercise or by adding CO₂ to the venous circulation with a membrane CO₂ exchanger. Moreover, in their discussion of these remarkable results, the authors stated that the tight coupling between ventilation and CO₂ flow was abolished by denervation of the carotid bodies, although the denervation data were not published in their report.

Nevertheless, these observations suggest that an enhancement of the amplitude and frequency of the arterial CO₂ oscillations that accompanies increased CO₂ flow to the lungs may be sensed by the carotid bodies, thereby providing a mechanism to explain the coincident changes in lactate production, increased CO₂, and hyperventilation observed during heavy exercise. In this regard, it is crucial that Hardarson and colleagues (4) test their hypothesis directly by demonstrating that denervation of the carotid bodies abolishes the ventilatory effects of the infused lactate; these experiments become even more urgent when viewed in the light of data showing that carotid body sensitivity to inhaled CO₂ is very low in anesthetized rats (3).

Substantial evidence against a carotid body contribution to the heavy exercise hyperventilation in other mammals, including humans, must also be considered when designing experiments to test the CO₂ oscillations hypothesis. First, the relationship between ventilation and CO₂ in exercising goats was not influenced significantly by carotid body denervation (8). Second, Jeyaranjan et al. (6) showed that hyperoxia did not significantly alter the ventilatory response to heavy exercise in human subjects. Third, intravenous infusions of dopamine (which inhibits carotid body chemosensitivity) in human subjects did not alter the hyperventilation of heavy exercise, even though hypoxic sensitivity at rest was reduced (5). Finally, it is important to point out that the hyperventilation of heavy exercise can be observed in the absence of a rise in the plasma lactate concentration. For example, Mateika and Duffin (7) showed that glycogen depletion by prior exercise led to a hyperventilatory response on a subsequent exercise test, even though changes in plasma lactate levels did not occur. Thus data in both animal models and human subjects show that the mechanism of the hyperventilatory response to heavy exercise is far from settled. At the very least, the data suggest that the threat to homeostasis is so profound in heavy exercise that several mechanisms capable of evoking a compensatory hyperventilation (e.g., carotid body sensing of K⁺ and/or norepinephrine, central motor command, "metaboreceptors," and so on; see Ref. 10) have been conserved in the ventilatory control system of mammals. Whether a mechanism linked to lactate oxidation (or to independent effects of the lactate anion) can be added to this list will await the results of future experiments.

	REFERENCES

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3.	Fukuda, Y., A. Sato, and A. Trzebski. Carotid chemoreceptor discharge responses to hypoxia and hypercapnia in normotensive and spontaneously hypertensive rats. J. Auton. Nerv. Syst. 19: 1-11, 1987[Medline].
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