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Published ahead of print on September 7, 2006, doi:10.1164/rccm.200606-842OC
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American Journal of Respiratory and Critical Care Medicine Vol 175. pp. 62-68, (2007)
© 2007 American Thoracic Society
doi: 10.1164/rccm.200606-842OC

Original Article

Antioxidants Increase the Ventilatory Response to Hyperoxic Hypercapnia

Spyros Zakynthinos, Paraskevi Katsaounou, Maria-Helena Karatza, Charis Roussos and Theodoros Vassilakopoulos

Department of Critical Care and Pulmonary Services, University of Athens Medical School, Evangelismos Hospital, Athens, Greece

Correspondence and requests for reprints should be addressed to Spyros G. Zakynthinos, M.D., Medical School of Athens University, Department of Critical Care and Pulmonary Services, Evangelismos Hospital, 45-47 Ipsilandou St., GR 106 75 Athens, Greece. E-mail: szakynthinos{at}yahoo.com


   ABSTRACT
TOP
 ABSTRACT
AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Rationale: The mechanisms by which chemoreceptors process carbon dioxide stimuli are poorly understood. Recent in vitro studies suggest a role of reactive oxygen species in central carbon dioxide chemoreception.

Objectives: We tested the hypothesis that antioxidant treatment modulates the ventilatory response to carbon dioxide in healthy humans, either during unloaded breathing or after strenuous resistive breathing.

Methods: In the first experiment of this randomized, double-blind, placebo-controlled study, 14 healthy males completed hyperoxic carbon dioxide rebreathing, received either antioxidants (vitamins E, A, and C for 2 mo, allopurinol for 15 d, and N-acetylcysteine for 3 d) (n = 7) or placebo (n = 7), and repeated rebreathing 3 mo later. In the second experiment, 18 healthy males completed a series of rebreathing tests before and after strenuous resistive breathing. Subjects repeated the same protocol 3 mo later, after they had received antioxidants (n = 9) or placebo (n = 9).

Main Results: After antioxidants, the sensitivity of the ventilatory (minute ventilation) response to carbon dioxide increased (mean [± SEM], 3.2 ± 0.5 vs. 1.7 ± 0.4 L/min/mm Hg; p < 0.001). Antioxidants also increased the sensitivity to carbon dioxide before and at 5, 30, and 120 min after resistive breathing (p = 0.01). This effect was entirely due to increased tidal volume. Antioxidants did not influence the breathing pattern during resting breathing or the rapid shallow breathing response to carbon dioxide at 5 min after resistive breathing.

Conclusions: Antioxidants, by augmenting the tidal volume, increase the sensitivity of the ventilatory response to carbon dioxide, either during unloaded breathing or after resistive breathing.

Key Words: central chemoreception • control of breathing • reactive oxygen species



   AT A GLANCE COMMENTARY
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Scientific Knowledge on the Subject
Recent studies have provided clues to the fundamental role of reduction–oxidation (redox) reactions and reactive oxygen species in central carbon dioxide chemoreception.

What This Study Adds to the Field
Antioxidants augment the tidal volume, thereby increasing the sensitivity of the ventilatory response to carbon dioxide in healthy humans during unloaded breathing and after resistive breathing.

 
A major defense of mammals to acute hypercapnia is a rapid increase in pulmonary ventilation to facilitate carbon dioxide removal, thereby maintaining acid–base homeostasis. This vital chemoreflex is mediated by both central and peripheral carbon dioxide/hydrogen ion chemoreceptors (1, 2). The mechanisms by which hypercapnic stimuli are processed are poorly understood (2, 3). Recent in vitro studies have provided clues to the fundamental role of reduction–oxidation (redox) reactions and reactive oxygen species in central carbon dioxide chemoreception (2–4). Because of the widespread effects of reactive oxygen species (5), oxidative stress may affect the ventilatory control by affecting not only central chemoreceptors but many other elements of the respiratory control system, including nonrespiratory systems that modulate the chemoreflexes (6).

Strenuous resistive breathing (which is encountered in obstructive lung diseases) increases the production of reactive oxygen species, both within the working respiratory muscles and in the extracellular and vascular compartments (7–9). Interestingly, strenuous resistive breathing leading to respiratory muscle fatigue (10–14) may alter the central chemoreceptor response (11–14) by either inducing rapid shallow breathing (11, 12) or decreasing sensitivity (slope) of the ventilatory response to carbon dioxide stimulation (13, 14) in the immediate recovery period after fatigue. Contribution of the increased oxidative stress in these changes has been suggested (7, 15, 16).

Therefore, the aim of the present randomized, double-blind, placebo-controlled study was to test the hypothesis that antioxidant treatment modulates the ventilatory response to carbon dioxide in healthy humans, either during unloaded breathing or after strenuous, fatiguing resistive breathing. Some of the results of this study have been previously reported in the form of an abstract (17).


   METHODS
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 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Methodologic details are available in the online supplement.

Subjects
Two groups of healthy male subjects volunteered for this study. Subjects were instructed to abstain from physical exercise, caffeine, and alcohol for at least 24 h before the experiments. The local ethics committee approved the protocol. All subjects gave written, informed consent.

Experiment I
The primary objective of this experiment was to examine the effect of antioxidants on the ventilatory and breathing pattern response to carbon dioxide stimulation during unloaded breathing. The secondary objective was to examine the effect of antioxidants on the breathing pattern during resting breathing.

A total of 14 subjects (36 ± 6 yr old) participated. Pulmonary function tests and venous and arterial blood sample collections, for measurement of redox status and acid–base balance, were performed on a single day before the main testing for Experiment I.

Each subject was studied twice, 3 mo apart, before and after either antioxidant (antioxidant group, 7 subjects) or placebo (placebo group, 7 subjects) supplementation. On the day of the study, after resting for 10 min, subjects breathed air through a mouthpiece connected to the experimental circuit. After 10 min of adaptation to the circuit, measurements were recorded over the subsequent 5 min to obtain the breathing pattern during resting breathing, and oxygen consumption and carbon dioxide production were measured. Subsequently, two carbon dioxide rebreathing tests were performed (separated by a 15-min rest period) and were averaged to reduce random variability. At 1 mo after the initial study, subjects were started on either antioxidant or placebo supplementation regimen. After completing the supplementation (2-mo duration), venous and arterial blood samples were collected, and an identical study as the first one was performed. The design of antioxidants or placebo administration was randomized and blinded to the subjects and researchers.

Experiment II
The objective of this experiment was to examine the effect of antioxidants on the ventilatory and breathing pattern response to carbon dioxide stimulation before and after strenuous resistive breathing.

A total of 18 subjects volunteered (antioxidant group, 9 subjects; placebo group, 9 subjects; 38 ± 4 yr old). The same protocol was used as in Experiment I, except for the following: on the day of the study, half an hour after the two consecutive baseline rebreathing tests, subjects were instructed to perform an inspiratory resistive breathing run (7, 15). The rebreathing tests were then repeated at 5, 30, and 120 min after the resistive breathing.

Respiratory Measurements
Carbon dioxide rebreathing.
The hyperoxic ventilatory response to hypercapnia was determined by Read's rebreathing method (18). Subjects breathed a gas mixture of 7% carbon dioxide balanced with oxygen.

Minute ventilation (ventilatory), tidal volume, and mean inspiratory flow responses to carbon dioxide were evaluated by relating end-tidal partial pressure of carbon dioxide with the respective variable during rebreathing using linear regression. The slopes of the regression lines were used for comparison. The relationship between minute ventilation and tidal volume (19) was used to quantify any change in the relative contribution of respiratory frequency and tidal volume to overall minute ventilation during rebreathing (13). A plateau in tidal volume was not reached during any of the tests, so that the minute ventilation–tidal volume relationship could be described by a single linear regression equation. An increase in slope or leftward shift indicates development of rapid shallow breathing and vice versa.

Inspiratory resistive breathing.
Measurement of maximal inspiratory pressure and inspiratory resistive breathing were performed as described previously (7, 15). During resistive breathing, the subjects breathed through a resistance while maintaining 80% of their maximal inspiratory pressure. A detailed description of the respiratory measurements is included in the online supplement.

Antioxidant and placebo supplementation.
Subjects in the antioxidant groups received a combination of oral antioxidants, including (7, 8): 200 mg vitamin E, 50,000 IU vitamin A, and 1,000 mg vitamin C per day for 60 d before the second study; 600 mg allopurinol per day for 15 d; and 2 g N-acetylcysteine per day for 3 d and 800 mg on the morning before the second study. Subjects in the placebo groups received placebos consisting of cellulose tablets and capsules manufactured by the local pharmacy (Lavipharm, Athens, Greece).

Blood redox and acid–base status.
Malondialdehyde, a product of lipid peroxidation (20), was measured in venous blood as an index of the level of oxidative stress. Acid–base balance and pH were measured in arterial blood.

Statistical Analysis
The minimum sample size was calculated based on 80% power and a two-sided 0.05 significance level (21). The sample size capable of detecting between-group difference of 1.2 L/min/mm Hg was estimated for the slope of the ventilatory response to carbon dioxide using the standard deviation from a previous study (13). The critical sample size per group was estimated to be seven subjects.

Differences in slopes and the other variables before and after antioxidants or placebo were compared using repeated-measures two-way analysis of variance (ANOVA). Differences in slopes before and after the resistive breathing were analyzed along two different lines: (1) slopes were compared using repeated-measures two-way ANOVA; (2) the areas under the curves (8) of the change in slope over time were compared using repeated-measures two-way ANOVA. The Tukey's honest significant difference test was used for post hoc comparisons. All statistical tests were performed at the two-sided 0.05 significance level. Values reported are means (± SEM).


   RESULTS
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 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Experiment I
Resting breathing.
Except for malondialdehyde levels, which decreased after antioxidants, no significant difference was observed in either group (Table 1).


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  		TABLE 1. BREATHING PATTERN, METABOLIC RATE, ARTERIAL ACID–BASE STATUS, AND BLOOD REDOX STATUS DURING RESTING BREATHING, BEFORE AND AFTER ANTIOXIDANT OR PLACEBO TREATMENT

 
Ventilatory response to carbon dioxide.
After antioxidant treatment, the slope of the ventilatory response to carbon dioxide stimulation increased almost twofold (Table 2; Figure 1), a response consistent in all subjects (Figure 2). The slopes of the mean inspiratory flow and tidal volume responses also increased after antioxidant treatment. No change in either slope or position (x intercept; data not shown) of the minute ventilation–tidal volume relationship was observed (Table 2; Figure 1), indicating that respiratory frequency change did not contribute to the increase of the ventilatory response after antioxidant treatment. No changes were detected in the placebo group (Table 2; Figure 2).


Figure 1
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  		Figure 1. Ventilatory and breathing pattern response to carbon dioxide in a representative subject, before and after antioxidants. Note that, after antioxidant treatment, the slope of the (A) ventilatory (i.e., minute ventilation), (B) mean inspiratory flow, and (C) tidal volume response to carbon dioxide increased, whereas the slope of the (D) minute ventilation–tidal volume relationship did not change. The minute ventilation–tidal volume relationship represents the relative contribution of respiratory frequency and tidal volume to overall minute ventilation during carbon dioxide stimulation. This finding indicates that respiratory frequency change did not contribute to the observed increase of the ventilatory response to carbon dioxide after antioxidant treatment. Open circles, before antioxidants; closed circles, after antioxidants.

 

Figure 2
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  		Figure 2. Ventilatory response to carbon dioxide of individual subjects, before and after antioxidants or placebo. Note the ability of (A) antioxidant, but not (B) placebo treatment, to increase the slope (sensitivity) of the ventilatory response to carbon dioxide. p Values are for the comparison between before and after treatment. Mean values are given in Table 2.

 

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  		TABLE 2. VENTILATORY AND BREATHING PATTERN RESPONSE TO CARBON DIOXIDE, BEFORE AND AFTER ANTIOXIDANT OR PLACEBO TREATMENT

 
Experiment II
Malondialdehyde levels decreased after antioxidants (6.19 ± 1.83 vs. 16.34 ± 2.44 µg/L; p < 0.001), whereas they did not change after placebo (19.21 ± 2.58 vs. 18.11 ± 2.56 µg/L).

Ventilatory response to carbon dioxide before and after resistive breathing.
Antioxidants, but not placebo, increased the slope of the ventilatory response to carbon dioxide stimulation throughout the experiment (p = 0.01 for the areas under the curve) (Figures 3A and 3D). This increase was due to the increased slope of the tidal volume response after antioxidants (p = 0.01 for the areas under the curve; Figures 3B and 3E). The slope (or the position—data not shown) of the minute ventilation–tidal volume relationship was not significantly different after antioxidants (Figures 3C and 3F), indicating that respiratory frequency change did not contribute to the observed increase of the ventilatory response after antioxidant treatment.


Figure 3
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  		Figure 3. Ventilatory and breathing pattern response to carbon dioxide at baseline and after inspiratory resistive breathing, before and after antioxidants or placebo. Note the ability of (A) antioxidants, but not (D) placebo, to increase the slope of the ventilatory response to carbon dioxide throughout the experiment (i.e., at baseline and at 5, 30, and 120 min after inspiratory resistive breathing) by increasing the (B) slope of the tidal volume response. Also note that (B and C) antioxidants, just like (E and F) placebo, did not influence the rapid, shallow breathing response to carbon dioxide at 5 min after resistive breathing (*p < 0.001 for the comparison with before antioxidants, as well as for the comparison with before and after placebo at the same time point; #p < 0.01 for the comparison with baseline and 30 and 120 min after resistive breathing; +p < 0.05 for the comparison with baseline and 30 and 120 min after resistive breathing). Symbols represent mean values and vertical lines depict SEM.

 
The configuration of the ventilatory and breathing pattern responses to carbon dioxide stimulation after resistive breathing compared with that before resistive breathing (baseline) was unaffected by antioxidant or placebo treatment. Indeed, in both antioxidant and placebo groups, either before or after treatment, this configuration was similar: the slope of the ventilatory response to carbon dioxide did not change significantly at any time points after the resistive breathing compared with baseline (Figures 3A and 3D). The breathing pattern response to carbon dioxide changed at 5 min after the resistive breathing; that is, the slope of the tidal volume response decreased (Figures 3B and 3E), whereas the slope of the minute ventilation–tidal volume relationship increased (Figures 3C and 3F), implying higher relative contribution of breathing frequency than tidal volume to overall minute ventilation (rapid shallow breathing). At 30 and 120 min after the resistive breathing, the breathing pattern returned to baseline. Results of inspiratory muscle strength are included in the online supplement (see Tables E1 and E2 in the online supplement).


   DISCUSSION
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The main finding of the present study is that antioxidant supplementation increased the sensitivity of the ventilatory response to carbon dioxide, either during unloaded breathing or after strenuous resistive breathing. This effect was entirely due to increased tidal volume. Antioxidants did not influence the breathing pattern during resting breathing or the rapid, shallow breathing response to carbon dioxide stimulation 5 min after resistive breathing.

Carbon Dioxide Chemoreception and Antioxidants
To our knowledge, the effect of antioxidants on the chemoreflex sensitivity to carbon dioxide in humans has never been evaluated before. Antioxidants increased the sensitivity of the ventilatory response. Because the oxygen consumption and carbon dioxide production (measures of metabolic rate) and the acid–base balance did not change, these factors could not be responsible for the observed increase in sensitivity. During hyperoxia, brain tissue carbon dioxide determines the ventilatory response to carbon dioxide (1, 18, 22–25). This increase in sensitivity could be the result of either greater load of carbon dioxide on the central chemoreceptors, as a consequence of excessive cerebral blood flow induced by antioxidants (26), or increased activity of the central chemoreceptors due to antioxidant-induced change in brain redox state. The first mechanism is not expected to explain the increased sensitivity to carbon dioxide, because it has been theoretically predicted (18, 24) and suggested from study findings (27) that the relationship between brain tissue carbon dioxide and end-tidal carbon dioxide remains unaffected by alterations of cerebral blood flow during rebreathing. The other mechanism, implicating the antioxidant-induced change in brain redox state with increased activity of the central chemoreceptors, has theoretical potential. Our finding could be explained by oxidative stress–induced suppression of the central chemoreceptors or their signaling cascade during hyperoxic carbon dioxide rebreathing. The reduction of oxidative stress with antioxidants could decrease this suppression, thus increasing stimulation of the central chemoreceptors and sensitivity to carbon dioxide. However, recent experiments in rat brain stem slices seem to contradict this mechanism, as they have shown that some carbon dioxide chemosensitive neurons are also excited by reactive oxygen species induced by hyperoxia (3, 4). Therefore, either our hypothesis involving the central chemoreceptors is wrong or the findings in rat brain stem slices (3, 4) do not apply to humans. Nevertheless, the overall effects of oxidative stress and antioxidant treatment on human central chemoreception remain rather uncertain, considering the interspecies differences, the presence of chemoreception at widespread sites within the hindbrain (28, 29), and the complexity of the system involving many different neuronal phenotypes (28, 29).

Although our intention was to examine the effect of antioxidants on the central chemoreflex sensitivity to carbon dioxide, we cannot exclude an effect of our antioxidant treatment on the peripheral arterial chemoreceptors. In this regard, another mechanism that could potentially explain our main finding of antioxidant-induced increased sensitivity to carbon dioxide implicates the effects of oxidative stress and antioxidants on both central and peripheral chemoreceptors during hyperoxia. Indeed, during hyperoxic breathing, minute ventilation may be the net output of reactive oxygen species–induced inhibition of peripheral chemoreceptors (30) and stimulation of central chemoreceptors (2–4). The reduction in oxidative stress with antioxidant treatment could suppress peripheral chemoreceptor response (i.e., inhibition) more than central chemoreceptor response (i.e., stimulation), resulting in a net increase of the sensitivity to carbon dioxide during rebreathing.

Antioxidants may act to change the ventilatory response to carbon dioxide anywhere along the chemoreflex arc, which, besides central chemoreceptors, includes spinal transmission and neuromuscular coupling. For example, in rats, reactive oxygen species reduce phrenic to diaphragm coupling (31), evidence consistent with our finding of antioxidant-induced increased sensitivity to carbon dioxide affecting tidal volume. Moreover, antioxidants may have effects on other systems, such as the sympathetic system (6), which, in turn, may alter the sensitivity of the chemoreflexes. The latter observation (6) is also consistent with our findings.

Notably, antioxidants increased the sensitivity of the ventilatory response by increasing the tidal volume component of minute ventilation, whereas respiratory frequency increase did not contribute to this ventilatory response. There are indications that different components of the respiratory central pattern generator control the amplitude (tidal volume) and timing (frequency, inspiratory and expiratory duration) of respiration (32, 33). Recent data suggest that this may also be the case in central chemoreception. Indeed, Li and Nattie (29) demonstrated that, by specifically lesioning the catecholamine neurones, which are carbon dioxide–sensitive chemoreceptors located in many regions, the ventilatory response to carbon dioxide was reduced which decreased the breathing frequency, whereas tidal volume was not affected. Therefore, if antioxidants have a central effect, they should exert their action in components of the central chemoreception that control the tidal volume.

The finding that antioxidants did not influence the resting breathing pattern suggests that redox state is not implicated in resting respiratory rhythmogenesis. Central chemoreception is widely regarded as occurring at sites anatomically and functionally distinct from those of respiratory pattern generators (1, 28, 32), which are predominantly responsible for the resting pattern of breathing (28, 32).

Resistive Breathing, Carbon Dioxide Chemoreception, and Antioxidants
In contrast to previous reports (13, 14), the strenuous resistive breathing of the present study did not decrease the central chemoreflex sensitivity, but, like other studies (11, 12), induced rapid, shallow breathing in response to carbon dioxide stimulation at 5 min after resistive breathing. This was followed by a subsequent return to the previous baseline breathing pattern. Antioxidants did not influence this rapid, shallow breathing response. However, just like during unloaded breathing, antioxidants increased the sensitivity of the ventilatory response after resistive breathing, the effect also being entirely due to an increased tidal volume.

The failure of antioxidant treatment to restore the rapid, shallow breathing response after resistive breathing suggests that oxidative stress is not predominantly responsible for this alteration in central chemoreflex. Other potentially responsible mechanisms include a behavioral response to muscular exertion due to resistive breathing (13), stimulation of respiratory muscle small afferents (34–36), and contractile respiratory muscle fatigue (11, 13, 14). Stimulation of respiratory muscle small afferents by strenuous contraction–induced metabolic changes in the respiratory muscles (37, 38) can result in rapid, shallow breathing (34–36). Interestingly, respiratory muscle small afferents may act by inducing beta-endorphin secretion (36, 38), which also induces rapid, shallow breathing. This effect could not be blunted by our antioxidant treatment, because beta-endorphin secretion is stimulated by lactic acidosis within the diaphragm (37, 38) rather than by oxidative stress. Finally, a decrease in respiratory muscle contractile force for a given neural output (contractile fatigue) in the immediate recovery period after strenuous resistive breathing has been reported to contribute to the observed rapid, shallow breathing (11, 13, 14), and is also supported by our finding of decreased force-generating capacity of the respiratory muscles after the resistive breathing sessions (Tables E1 and E2).

Methodologic Considerations
We performed hyperoxic rebreathing experiments for two reasons. First, because our objective was to examine the effect of antioxidants on central chemoreception, and hyperoxia is deemed to suppress the activity of peripheral chemoreceptors (1). Second, because high inspired fraction of oxygen, which can result in accumulation of reactive oxygen species (2), is routinely used in clinical practice. Possible interactions between reactive oxygen species induced by hyperoxia and carbon dioxide are of interest because carbon dioxide retention during hyperoxia can occur as the result of certain respiratory diseases (e.g., chronic obstructive pulmonary disease and subsequent oxygen therapy) or when hyperbaric gases are breathed, as during underwater diving (22). It should also be noted that hypoxia may also induce reactive oxygen species formation (39).

As in previous studies (7, 8), we used a cocktail of scavengers and inhibitors of reactive oxygen species–producing enzymes. This antioxidant cocktail was effective in blunting the cytokine response to resistive breathing (7) or bicycle exercise (8) in normal volunteers. Malondialdehyde is a surrogate marker of oxidative stress, and the reduction of its plasma levels measured in our subjects after antioxidant treatment indicates that the antioxidant cocktail we administered actually reduced the oxidative stress. However, pharmacologic effects of this cocktail unrelated to oxidative stress attenuation cannot be excluded.

Physiologic and Clinical Significance
Oxygen is required to sustain life, but too much oxygen can result in oxidative stress (2). Increase in arterial carbon dioxide during hyperoxia can occur in diseases characterized by increased respiratory load (e.g., chronic obstructive pulmonary disease and subsequent oxygen therapy) or during unloaded breathing when hyperbaric gases are breathed, as during underwater diving (22). Besides, hypoventilation induced mainly by low tidal volume contributes to this carbon dioxide retention (22, 40). The findings of the present study suggest a role of oxidative stress in carbon dioxide chemoreception during hyperoxia under either unloaded or loaded respiratory conditions. As antioxidants can increase the sensitivity to carbon dioxide, their administration in the above-mentioned conditions could minimize hypoventilation, thus decreasing carbon dioxide retention. However, because the carbon dioxide sensitivity curve intersects with the flat portion of the metabolic hyperbola (23), the possible benefits of antioxidants in patients are likely to be limited.

In conclusion, in healthy humans and during hyperoxia, antioxidant supplementation increased the sensitivity to carbon dioxide both during unloaded breathing and after strenuous resistive breathing, and this increase in sensitivity was due to increased tidal volume.


   FOOTNOTES
 
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Originally Published in Press as DOI: 10.1164/rccm.200606-842OC on September 7, 2006

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form June 23, 2006; accepted in final form September 6, 2006


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 DISCUSSION
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