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1 School of Human Kinetics2 Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada
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Abstract |
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was determined using a ramped cycle exercise test. Maximal exercise data were not different (P > 0.05) between SDIH and LDIH groups or following intermittent hypoxia. Minute ventilation, tidal volume and respiratory frequency were compared at 20, 40, 60, 80 and 100% of 
. There was no difference in the ventilatory responses at any intensity of exercise following the intermittent hypoxia period. The HVR was significantly increased following the intermittent hypoxia intervention (P < 0.05) but was not different between SDIH and LDIH (P > 0.05). The relationships between HVR and 
were non-significant on day 1 (r
= 0.30) and day 12 (r
= 0.47; P > 0.05). Our findings point to a lack of functional significance of increasing HVR via intermittent hypoxia on ventilatory responses to exercise at sea level.
(Received 15 September 2005;
accepted after revision 25 October 2005; first published online 1 November 2005)
Corresponding author A. W. Sheel: Health and Integrative Physiology Laboratory, School of Human Kinetics, The University of British Columbia, 210-6081 University Blvd, Vancouver, BC, Canada, V6T-1Z1. Email: bill.sheel{at}ubc.ca
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Introduction |
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hyperpnoea and hypocapnia are present at the same time that lactacidosis occurs. Strong humoral stimuli (H+, K+ and catecholamines) increase in arterial blood in parallel with the hyperpnoea of heavy exercise. It is well known that carotid chemoreceptors are excited by all three of these stimuli, implying that they probably contribute to the hyperpnoea. The gain of the response to each of these stimuli is not substantial, however, and increasing lactacidosis is not required for the hyperventilatory response (Kaufman & Forster, 1996). In fact, many data do not support the theory that the hyperpnoea of heavy exercise is mediated by alterations to arterial levels of blood-borne stimuli and subsequent stimulation of the carotid bodies (Bisgard et al. 1982; Forster et al. 1983). For instance, in the carotid body-denervated pony, the hyperventilatory response to heavy exercise is enhanced (Pan et al. 1986). This is consistent with the hypothesis that the net output from the carotid chemoreceptors is not excitatory and may even be inhibitory to respiratory motor output and to the ventilatory response, and that the primary drive to exercise hyperpnoea is found in extra-chemoreceptor sources that are linked to locomotion (Dempsey et al. 1995). The present consensus is that the carotid chemoreceptors provide a fine-tuning function for alveolar ventilation during exercise (Whipp, 1994; Dempsey et al. 1995), rather than a primary drive for exercise hyperpnoea. It has been suggested that the carotid bodies may be required to detect oscillations of arterial pH (pHa), carbon dioxide (PaCO2) and oxygen (PaO2) tension within breaths, and that during exercise these oscillations may be enhanced and contribute to the ventilatory response (Yamamoto & Edwards, 1960; Saunders, 1980). There are three lines of evidence to support this concept: (i) within-breath changes are altered by electrically induced ‘exercise’ (Cross et al. 1982); (ii) carotid chemoreceptor activity has been shown to oscillate (Black & Torrance, 1971); and (iii) changes in the oscillations influence breathing (Black et al. 1973; Band et al. 1980; Saunders, 1980).
We (Foster et al. 2005) and others (Garcia et al. 2000; Katayama et al. 2001; Townsend et al. 2002) have shown that exposure to intermittent hypoxia enhances the human hypoxic ventilatory response (HVR) at rest. Exposure to episodic hypoxia and the enhanced HVR is associated with an augmented carotid sensory response to acute hypoxia (Peng et al. 2001), but it is not clear whether this augments ventilation during normoxic exercise. It has recently been shown that hypobaric intermittent hypoxia (432 mmHg for 1 h day–1 for 7 days) did not affect ventilation at 40, 70 or 100% of cycling 
(Katayama et al. 2002). However, this may reflect the type and pattern of the intermittent hypoxic stimulus (Serebrovskaya et al. 1999; Peng & Prabhakar, 2004; Townsend et al. 2005). For example, it has been shown that rats exposed to 10 days of short-duration intermittent hypoxia (15 s of 5% O2 at 5 min intervals, 8 h day–1) have an enhanced hypoxic chemosensitivity, while those exposed to long-duration hypobaric intermittent hypoxia (4 h day–1 at 
300 mmHg) do not (Peng & Prabhakar, 2004). It is not clear what the effects of different types of intermittent hypoxia have on human exercise ventilation.
If enhanced oscillations in PaO2 contribute to exercise hyperpnoea, and frequent alternations between normoxia and hypoxia increase hypoxic chemosensitivity, then short-duration intermittent hypoxia, but not long-duration intermittent hypoxia, may enhance exercise ventilation. Thus, the primary purpose of this study was to determine whether short-duration intermittent hypoxia, and the subsequent augmentation of HVR, would lead to an increase in ventilatory responses during exercise at sea level. It was hypothesized that subjects exposed to short-duration intermittent hypoxia would have a greater increase in the ventilatory response to exercise compared to those exposed to long-duration intermittent hypoxia.
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Methods |
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This study was conducted in conjunction with a study designed to examine the effects of intermittent hypoxia on resting ventilatory, cardiovascular and cerebral responses to hypoxia (Foster et al. 2005). The data in the present study were also used for analysis of the effects of intermittent hypoxia on the ventilatory responses to normoxic exercise. Of the 18 men who participated in the previous study, 17 completed the present study. All experimental procedures and protocols were approved by the Clinical Screening Committee for Research of the University of British Columbia and conformed to the Declaration of Helsinki. Active, healthy male volunteers provided written informed consent prior to participating in the investigation. All subjects had normal cardiopulmonary function and were excluded from participation if they had been diagnosed with asthma or sleep apnoea, had a history of smoking, or if they were hypertensive (systolic blood pressure > 140 mmHg; diastolic blood pressure > 90 mmHg). All subjects were life-long residents at sea level and had not sojourned to high altitude (> 3000 m) in the year prior to testing. None of the subjects participated in breath-hold diving or trained as endurance athletes, since this has been reported to affect ventilatory responses to hypoxia and hypercapnia (Byrne-Quinn et al. 1971; Ferretti, 2001).
Experimental protocol
Participants reported to the laboratory 4 h post meal consumption and after abstaining from caffeine ingestion for the preceding 24 h. Subjects completed informed consent forms, followed by anthropometric and pulmonary function measures. As previously described (Foster et al. 2005), subjects were then exposed to a total of 10 30 min isocapnic intermittent hypoxic exposures throughout a 12 day period. Subjects were randomly assigned to short-duration isocapnic intermittent hypoxia (SDIH; fractional inspired O2, FIO2 = 12% for 5 min followed by 5 min of normoxia, repeated for 1 h) or long-duration intermittent hypoxia (LDIH; FIO2 = 12% for 30 min). Subjects performed an incremental cycle exercise test to exhaustion on days 1 and 12.
Pulmonary function
Subjects performed three forced vital capacity (FVC) manoeuvres using a calibrated spirometer (Spirolab II, Medical International Research, Roma, Italy). Forced vital capacity, forced expiratory volume in 1 s (FEV1.0), and the ratio of FEV1.0 to FVC (FEV1.0/FVC) were assessed in accordance with standardized procedures (A.T.S., 1995).
Maximal cycle exercise test
Maximal oxygen consumption was determined using a ramped exercise test (30 W min–1) on an electronically braked cycle ergometer (Excalibur, Lode, Groningen, Netherlands). Metabolic and ventilatory parameters were recorded using a calibrated open-circuit system (Physio-Dyne, Max-1, Fitness Instrument Tech., New York, NY, USA). Heart rate was measured using a telemetric monitoring system (S410, Polar Electro Inc., Kempele, Finland). In addition to volitional exhaustion, all subjects fulfilled at least two of the following criteria for 
: (i) heart rate 
220 – age; (ii) respiratory exchange ratio 1.10; and (iii) no further increase in 
with increasing workload.
Ventilatory responses to hypoxia
The HVR was assessed by previously described methods (Koehle et al. 2005). Subjects breathed room air from a mixing chamber, and 100% N2 was gradually added to the inspiratory circuit to evoke a gradual drop in arterial oxyhaemoglobin saturation (SaO2) to 75% over an approximate 5 min period. Arterial oxyhaemoglobin saturation was measured at the finger using a pulse oximeter (3740, Ohmeda, Louisville, CO, USA). Isocapnia was maintained during the test by the manual addition of CO2 to the inspiratory circuit. End-tidal partial pressure of CO2 (PET,CO2) was sampled at the mouth and analysed using an infrared CO2 analyser (CD-3 A, AEI, Pittsburgh, Pennsylvania, USA). Resting PET,CO2 was determined at the beginning of each day and maintained throughout experimentation. The FIO2 was determined by analysing gas sampled from the proximal side of the inspiratory valve (S-3 A, AEI, Pittsburgh, PA, USA). Inspired minute ventilation 
was plotted as a function of SaO2, and the slope of the linear regression was taken to represent the HVR. The relationship between 
and SaO2 was considered acceptable when linearity was demonstrated. Ventilatory and SaO2 data were acquired at 200 Hz using an analog-to-digital converter (Powerlab/16SP ML 795, ADInstruments, Colorado Springs, CO, USA) interfaced with a personal computer and stored for subsequent analysis. Commercially available software was used to analyse variables (Chart v5.02, ADInstruments).
Statistical analysis
All data are expressed as means ± S.D. unless otherwise noted. Statistical software (Statistica v6.1, Statsoft Inc., Tulsa, OK, USA) was applied to detect differences using repeated measures analysis of variance procedures. When significant F ratios were detected, Tukey's post hoc analysis was applied to determine where the differences lay. Pearson product moment correlations were implemented to determine relationships between selected dependent variables. The level of significance was set at P < 0.05 for all statistical comparisons.
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Results |
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All subjects completed 10 intermittent hypoxic exposures over the 12 day period. Physical attributes and pulmonary function data are shown in Table 1. SDIH subjects were not different from LDIH subjects based on age, mass or pulmonary function. The SDIH group was slightly but significantly taller than the LDIH group (P < 0.05).
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Table 2 displays the maximal exercise data for pre- and post-exposure to intermittent hypoxia. Maximal exercise data were not different between SDIH or LDIH groups or between pre- and postintermittent hypoxia. Minute ventilation, tidal volume (VT) and respiratory frequency (fb) were compared at 20, 40, 60, 80 and 100% of 
(Fig. 1). There was no difference in the ventilatory responses at any intensity of exercise following the intermittent hypoxia period. Individual and group mean HVR data for SDIH and LDIH are displayed in Fig. 2. There were significant increases in HVR after 12 days of intermittent hypoxic exposure regardless of the type of intermittent hypoxic exposure, with no statistical differences between SDIH and LDIH. During HVR testing we were able to maintain PET,CO2 within ±1–2 mmHg of resting values for all subjects. The relationships between HVR and 
were non-significant on day 1 (r
= 0.30) and day 12 (r
= 0.47; P > 0.05).
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Discussion |
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Exercise responses
This study was designed to determine whether bouts of intermittent hypoxia would lead to adaptive changes in the integrated ventilatory response to normoxic exercise in humans. Small fluctuations in PaO2 (
3–5 mmHg; Ward et al. 1987) that occur during exercise have been hypothesized to present an ‘error signal’ that is sensed by the peripheral chemoreceptors, whereby the chemoreceptors may provide a fine-tuning function for alveolar ventilation during exercise. We hypothesized that augmentation of the HVR via SDIH would result in a proportional rise in minute ventilation for a given exercise intensity. Our rationale for the present study was that, because peripheral chemoreceptors may contribute to the modulation of ventilation during exercise (Whipp, 1994; Dempsey et al. 1995), a relationship between HVR and exercise ventilation would exist. Indeed, it has been shown that HVR is significantly correlated with submaximal exercise ventilation after 3–4 days of live-high train-low altitude acclimatization (Townsend et al. 2005). In addition, significant increases in submaximal exercise ventilation in noromoxia have been seen following exposure to hypoxia (3000 m, 8–10 h night for 11 days; Gore et al. 2001). However, these findings are in contrast with those of Katayama et al. (2004), who recently demonstrated a significant lowering of 
and heart rate, but not 
, during submaximal running in trained runners after short-term normobaric hypoxia (FIO2
= 12.3%; 3 h day–1 for 14 days).
We observed a significant increase in HVR with no concomitant change in the exercise ventilatory response. The increase in HVR was variable between subjects (see Fig. 2), but there was no relationship between changes in HVR and ventilatory responses to exercise. We found no differences in the ventilatory response at any intensity of exercise for 
, fb and VT. Furthermore, maximal 
, 
, ventilatory equivalents for O2 and CO2, 
, peak power and heart rate were not different following intermittent hypoxia. Our results are consistent with the finding that ventilatory responses are unaltered by exposure to intermittent hypoxia during submaximal steady-state exercise (Katayama et al. 2004) or incremental exercise (Katayama et al. 2002). Unique to our study was that the augmentation of HVR by two distinct patterns of intermittent hypoxia had no effect on exercise ventilation.
Why did we and others (Katayama et al. 2002, 2004) not observe a change in the ventilatory responses to exercise despite a significant increase in HVR, while others (Gore et al. 2001; Townsend et al. 2005) have? It is difficult to reconcile these contradictory findings, but several possible explanations exist. First, we maintained isocapnia during our experimental intervention, whereas some studies have been conducted in hypobaric conditions or at high altitude, with a resultant fall in CO2 (Gore et al. 2001; Townsend et al. 2005). It has been suggested that persistent hyperventilation upon removal from the hypoxic stimulus is dependent on hypocapnia (Engwall & Bisgard, 1990; Bisgard & Forster, 1996; Townsend et al. 2005). While we demonstrated a significant increase in HVR, the maintenance of isocapnia during the hypoxic exposures used in this study may partly explain the lack of effect on exercise ventilation, as has previously been reported. Second, the oscillations in PaO2 may have been small enough to be ‘tolerated’, given that the ventilatory response to exercise is governed by the principle of minimal effort, in which activation of the respiratory musculature is a coordinated effort to maintain adequate alveolar ventilation and minimize the work of breathing (Vidruk & Dempsey, 1980). Thus, it may have been energetically costly to increase respiratory muscle activity to offset the fluctuations in PaO2, since this can have consequences for the distribution of cardiac output (Harms et al. 1997; Sheel et al. 2001). Third, it may have been unnecessary to increase alveolar ventilation. Although we did not measure PaO2 or SaO2 during exercise, it is unlikely that our subjects developed significant exercise-induced arterial hypoxemia (EIAH). Arterial O2 desaturation of 3–15% below resting levels has been observed to occur at or near maximum exercise intensities in highly trained endurance athletes, whereas untrained and moderately trained males, such as those tested in this study, do not experience EIAH (Powers et al. 1988). Fourth, the type and duration of exposure to hypoxia used in the present study may not have been sufficient to elicit a functional change in the ventilatory control system, despite a significant increase in HVR. Exercise ventilation at sea level has been shown to increase following longer exposure periods (Rodriguez et al. 1999). We cannot exclude the possibility that a longer exposure period or different pattern of intermittent hypoxia may have elicited a change in exercise ventilation. Fifth, it remains possible that altering chemosenstivity has an effect on exercise ventilation but that it is overridden or masked by other controlling mechanisms. From the point of view of experimental design, it is extremely difficult (if not impossible) to significantly manipulate a single regulatory pathway of ventilatory control (Forster, 2000). In our model, we experimentally manipulated one potential pathway and measured exercise ventilation in healthy, intact humans. It is well known that redundancy exists within the ventilatory control system. Indeed, strong support of neurally originating mechanisms comes from studies of decerebrate cats exercising on a treadmill (Eldridge et al. 1985). In addition, a neural signal is known to originate in contracting muscles (Bennett, 1984; Pan et al. 1990). In the present study, a descending neural signal (i.e. ‘central command’) originating from the motor cortex or a neural signal from contracting muscles was presumably the same between the two experimental conditions. As such, these ‘neural’ respiratory influences may be of greater importance than oscillations in PaO2. In addition, hypocapnia occurs during heavy exercise. It is possible that reduced PaCO2 inhibits any potential rise in ventilation and therefore masks the rise that we may have expected to see. It is likely that there are many sufficient regulatory mechanisms, each of which in a given, isolated circumstance, explains the whole phenomenon, and when they act simultaneously, they mask each other (Yamamoto, 1977).
HVR and maximal O2 consumption
From the available cross-sectional data, it is attractive to suggest that elite athletes have a diminished HVR (Byrne-Quinn et al. 1971; Scoggin et al. 1978; Schoene et al. 1981). However, low hypoxic chemosensitivity is not a uniform trait among endurance athletes (Townsend et al. 2002; Guenette et al. 2004). The relevance of a ‘blunted’ HVR in athletes, relative to untrained individuals, is not clear, but some have suggested that it may mean less ventilation during exercise and that the reduced ventilatory demand may produce less dyspnoea during exercise (Scoggin et al. 1978). Importantly, a causal link between endurance training and diminished chemosenstivity has not been established. It has been demonstrated that intensive endurance training at sea level does not affect the HVR in untrained subjects (Levine et al. 1992). This lack of change to HVR was accompanied by an exercise-training induced rise in 
of 15%. Conversely, others have found a decrease in HVR (pretraining, 0.49 l min–1
SaO2–1; post-training, 0.25 l min–1SaO2–1) after modest sea level endurance training that elicited a small, but statistically significant, increase in 
(4 ml kg –1 min–1; Katayama et al. 1999). A physiological mechanism(s) to explain why increasing aerobic power might result in a decrease in HVR is lacking. Further investigation is required to clarify these contradictory results (Levine et al. 1992; Katayama et al. 1999), but the findings from the present study also suggest a lack of clear association between HVR and 
. We demonstrated a significant increase in HVR (see Fig. 2) with no change in 
. If HVR and aerobic capacity are functionally coupled, then presumably altering HVR should have a measurable effect on 
. Alternatively, it remains possible that increasing aerobic power has effects on ventilatory control, whereas changing ventilatory control has no effect on oxygen uptake. However, our results, coupled with those of others (Levine et al. 1992) where HVR or 
were experimentally manipulated, suggest a more fortuitous correlative relationship between HVR and 
than one of causation. Additional experimental studies are necessary to provide an appropriate answer to the question of linkage between aerobic power, endurance training and hypoxic chemosenstivity.
Methodological considerations
We used a ramped cycle exercise test. As such, the submaximal ventilatory measures were not obtained in a steady state. While this also may have influenced our results, our findings are in good agreement with those of others (Katayama et al. 2003, 2004), which would suggest that the exercise test per se did not influence our results.
There can be large variability associated with day-to-day HVR measures. It has been reported that the coefficient of variation for HVR can be as high as 62.9% (Beidleman et al. 1999). Using similar methods to those described in this study, we performed repeated testing over five consecutive days and found the mean individual coefficient of variation to be 27 ± 4% (Koehle et al. 2005). In the present study we documented a statistically significant increase in HVR which exceeded 27% (see Fig. 2) and so the increase was not due only to day-to-day variation.
We used healthy but relatively untrained subjects (i.e. low aerobic power; 
. Our subjects were selected because of their low training status. It is possible that we might have obtained different results with a subject population with a higher 
and we cannot rule this out.
We did not have a direct measurement of PaO2 oscillations. Direct measures of oscillations in pHa to reflect respiratory oscillations in PaCO2 have been made during mild exercise in humans (Band et al. 1980). However, to our knowledge direct oscillation measures of PaO2 have not been made in exercising humans for technical reasons. Despite this, from studies examining breath-by-breath gas exchange kinetics during exercise it is clear that there are oscillations in the end-tidal partial pressure of O2 (PET,O2; and presumably PaO2; Ward et al. 1987). Although we did not measure PET,O2, we can presume that the cyclical variations in PET,O2 experienced by subjects in our study were comparable to those in other studies and that the carotid bodies would ‘see’ these small fluctuations in PaO2.
Conclusions
We increased hypoxic chemosensitivity using two types of intermittent hypoxia. While both increased the HVR, neither protocol had a measurable effect on exercise ventilation or maximal oxygen consumption. Our findings suggest that the functional relevance of a high or low HVR is minimal with respect to sea level ventilation. However, the well-known and important role of neurally originating mechanisms of ventilatory control may mask any potential effect of increased HVR.
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, minute ventilation; VT, tidal volume; fb, respiratory frequency; 
, maximal oxygen consumption.