Abstract
We tested the hypothesis that the promotion of hypoxic ventilatory responsiveness (HVR) and/or hypercapnic ventilatory responsiveness (HCVR) mostly acting on the carotid body with a changing work rate can be attributed to faster hypoxic ventilatory dynamics at the onset of exercise. Eleven subjects performed a cycling exercise with two repetitions of 6 minutes while breathing at FIO2 = 12%. The tests began with unloaded pedaling, followed by three constant work rates of 40%, 60%, and 80% of the subject's ventilatory threshold at hypoxia. Reference data were obtained at the 80% ventilatory threshold work rate during normoxia. Using three inhaled 100% O2 breath tests, a comparison of hypoxia and normoxia revealed an augmentation of HVR in hypoxia, which then significantly increased proportionally with the increase in work rate. In contrast, HCVR using three inhaled 10% CO2 breath tests was unaffected by the difference in work rate at hypoxia but did exceed its level at normoxia. The decrease in the half-time of hypoxic ventilation became significant with an increase in work rates and was significantly lower than at normoxia. Using a multiregression equation, HVR was found to account for 63% of the variance of hypoxic ventilatory dynamics at the onset of exercise and HCVR for 9%. O2 uptake on-kinetics and off-kinetics under hypoxic conditions were significantly slower than under normoxic conditions, whereas they were not altered by the changing work rates at hypoxia. These results suggest that the faster hypoxic ventilatory dynamics at the onset of exercise can be mostly attributed to the augmentation of HVR with an increase in work rates rather than to HCVR. Otherwise, O2 uptake dynamics are affected by the lower O2, not by the changing work rates under hypoxic conditions.
With decreased inspired O2 concentrations, faster dynamics in V̇e at the onset of exercise are indicative of an increased chemoreceptor drive via the carotid body (1, 2). However, Sherrill and Swanson (3) have shown that, at rest, hypoxic ventilatory responsiveness (HVR), the relevant chemoreflex drive, is not related to the time constant for V̇e dynamics at the onset of exercise under normoxic conditions. Regarding the alteration of HVR with exercise, HVR can be increased with an increase in work rate (4, 5), suggesting that muscular exercise produces an enhanced ventilatory responsiveness to hypoxia. However, it is unclear whether hypoxic exercise ventilatory dynamics during the transient phase could be altered by a change in work rate and additionally whether they are related to HVR. Also, regarding hypercapnic ventilatory responsiveness (HCVR), some studies have demonstrated a large increase in HCVR during light or moderate exercise (6–9), whereas others have reported that HCVR is unaffected by exercise (10–13). It has not been shown whether the changes in HCVR can be related to hypoxic exercise hyperpnea during the transient phase of exercise regardless of work rate. In addition, even though patients with congenital central hypoventilation syndrome had clearly abnormally low or absent HCVR, the ventilatory responses in these patients during the onset of submaximal exercise were very similar to those of normal subjects and were accompanied by a small increase in arterial Pco2 during a steady state of exercise (14), suggesting that mechanisms other than respiratory chemoreception (HCVR or HVR) can increase ventilation in proportion to CO2 output (V̇co2) during exercise. Therefore, we should consider that both the humoral factors (i.e., Po2 and Pco2) acting on the peripheral chemoreceptors and the neurologic factors partly originating from the muscle chemoreflex are complexes modified to hypoxic exercise hyperpnea during the transient phase of exercise.
Hypoxia speeds up the dynamics of V̇co2 and V̇e (1, 15, 16) and slows the dynamics of O2 uptake (V̇o2) (1, 17–19). Our interest is in how changes in the work rate might affect V̇o2 dynamics at hypoxia. Although previous studies suggested that there were no alterations in V̇o2 dynamics caused by changes in work rates under normoxic conditions, the experimental verifications needed to account for the effect of independent factors such as mechanical work rates on V̇o2 dynamics at hypoxia as well as at normoxia are scarce.
Therefore, our purpose in this study was to clarify the relative contributions of HVR, HCVR, and another factor (e.g., assuming a neurogic mechanism other than the humoral factor) in the stimulus responsible for exercise hyperpnea at hypoxia.
Eleven healthy male subjects who were 21–38 years old participated in the study. Their individual characteristics are given in Table 1
VTh | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| V̇O2 (ml · kg−1 · min−1) | WR (W) | |||||||||
| Subject Number | Weight (kg) | Height (cm) | Age (yr) | FIO2 = 0.12 | FIO2 = 0.21 | FIO2 = 0.12 | FIO2 = 0.21 | |||
| 1 | 74.0 | 181 | 22 | 15.7 | 23.2 | 134 | 207 | |||
| 2 | 60.0 | 163 | 25 | 13.8 | 20.5 | 100 | 158 | |||
| 3 | 60.0 | 163 | 23 | 20.3 | 25.0 | 100 | 131 | |||
| 4 | 71.0 | 175 | 30 | 13.6 | 18.5 | 86 | 125 | |||
| 5 | 78.3 | 175 | 23 | 13.5 | 20.5 | 79 | 131 | |||
| 6 | 75.0 | 170 | 38 | 10.0 | 15.3 | 60 | 115 | |||
| 7 | 57.2 | 171 | 19 | 17.2 | 22.4 | 89 | 116 | |||
| 8 | 65.5 | 163 | 19 | 18.2 | 27.3 | 114 | 171 | |||
| 9 | 80.0 | 165 | 21 | 16.5 | 23.9 | 110 | 159 | |||
| 10 | 74.0 | 176 | 23 | 15.1 | 22.7 | 118 | 177 | |||
| 11 | 54.0 | 168 | 21 | 14.6 | 21.9 | 79 | 119 | |||
| Mean | 68.1 | 170 | 24.0 | 15.3 | 21.9 | 97 | 146 | |||
| SEM | 2.4 | 1.5 | 1.2 | 0.6 | 0.7 | 5.1 | 7.7 | |||
Subjects performed both incremental and constant exercise tests on an electromagnetically braked cycle ergometer (RS-232c; Combi, Tokyo, Japan), which was modified to permit computer control of the workload. First, the subjects performed the incremental exercise until reaching approximately 80–90% exhaustion (e.g., heart rate of more than 160 beats per minute) while inspiring oxygen concentrations of 12% and 21%, respectively, on separate days. Subsequently, we determined the ventilatory threshold (VTh) at which the ratio of ventilation to oxygen uptake (i.e., V̇e/V̇o2) and the end-tidal Po2 start to increase without an increase in or a decrease in end-tidal Pco2, as well as the point of a nonlinear increase in V̇e (20, 21). In the effort to avoid metabolic acidosis under hypoxic conditions, the determination of VTh is more important than the peak V̇o2. Second, for constant exercise, three work rates, set at 40%, 60%, and 80% of VTh under hypoxic conditions, were used to focus on ventilatory and gas-exchange dynamics at the onset of exercise. On 2 separate days, HVR and HCVR were tested during exercise after obtaining the steady-state values. The exercise protocol involved two repetitions of constant exercise for 6 minutes and unloaded pedaling for 6 minutes at each work rate. In addition, the reference experiment with 80% VTh work rate at hypoxia was performed at normoxia (FiO2 = 21%). Ventilation during 80% VTh work rate at normoxia was approximately equal to ventilation during 60% VTh at hypoxia.
We used three different work rates for constant exercise. The subjects breathed through a mouthpiece with a three-way respiratory balloon valve (C3945; Arco-system, Chiba, Japan). A mass-flow sensor (type AB; Minato Medical Sciences, Osaka, Japan) was fitted to the expiratory port of the valve to record expiratory airflow continuously, which was calibrated before each experiment with a 3-L syringe at three different flow rates. Vt and V̇e were calculated by integrating the flow tracings recorded at the mouth of the subject. We confirmed that the sensitivity of the hot wire anemometer did not alter with changes in gas composition over the range of physiologic flow variations. Expiratory Po2 and Pco2 were determined by mass spectrometry (WSMR-1400; Westron, Chiba, Japan) from a sample drawn continuously from the inside of the mouthpiece at 1 ml/second; the loss of volume, however, was neglected in our calculations. Precision-analyzed gas mixtures were used to calibrate the mass spectrometer. The volumes, flows, Pco2, and Po2 at the mouth were recorded in real time with a 50-Hz sampling frequency using a computerized online breath-by-breath system (AE-280; Minato Medical Sciences). Breath-by-breath V̇e (BTPS), V̇o2 (STPD), V̇co2 (STPD), the respiratory exchange ratio, and end-tidal Pco2 (PetCO2) and Po2 (PetO2) were determined. Digital data for each test were displayed online and were also stored on a computer hard disk (BX; NEC, Tokyo, Japan). SaO2 was continuously monitored by pulseoxymeter (Biox 3740; Ohmeda, Amsterdam, The Netherlands) at the earlobe.
To characterize more precisely the kinetic behavior of ventilatory and gas-exchange variables under each condition, breath-by-breath V̇e, V̇o2, and V̇co2 data obtained during two repetitions were linearly interpolated separately at 1-second intervals and then superimposed and ensemble averaged to obtain a single data for each subject.
To evaluate mathematically and to compare the gas-exchange variables during the on-transition and off-transition in each condition, the values obtained for each experiment during hypoxic exercise were evaluated by fitting a monoexponential function of the type
 |
To compare V̇e, V̇o2, and V̇co2 non-dynamics and off-dynamics under each experimental condition, Equation 1 was solved to calculate the time necessary to reach 50% (t1/2, corresponding to the half-time of the response) of the difference between the baseline (unloaded pedaling) and the new asymptotic value obtained during hypoxic exercise. The t1/2 value has been reported to be an adequate indication of metabolic activity in working skeletal muscle (22, 23).
Three breaths of pure O2 were used to measure the peripheral chemoreceptor O2 drive (i.e., HVR) during exercise at various work rates under hypoxic conditions (24). Subjects were given less than 3 minutes of exercise to achieve the presumed steady-state conditions. This was verified during subsequent analysis by ensuring baseline ventilation over the entire period of administration. After obtaining the steady state for each test, 100% O2 was abruptly switched into the inspiration phase without the subject's anticipation. After three respiratory cycles, the previous gas mixture (i.e., 12% FiO2) was resubstituted. The procedure was repeated twice, allowing sufficient time after each procedure for V̇e to return to its prior control (i.e., steady state) level. The nadir of the decrease in V̇e after the switch to hyperoxic gas was calculated by averaging the two to three breaths (ΔV̇eo). ΔV̇eo/ΔSaO2 (L · min−1 · % −1) was defined as the ratio (slope) of the transient decrement in V̇e consequent to the three breaths of 100% O2 breathing, that is, ΔV̇eo divided by the change in SaO2. Reference data were obtained at 80% VTh work rate under normoxic conditions.
The measurement of hypercapnic ventilation (i.e., HCVR) at hypoxia was also determined by allowing three breaths of 10% CO2 (i.e., 10% CO2 + 12% O2 + N2 balance). This test was synchronized to the inspiration phase with an abrupt switch to 10% CO2 without the subject's knowledge. The HCVR under hypoxic conditions was also achieved after obtaining a steady-state in metabolic activity during hypoxic exercise. The procedure was repeated two times, allowing sufficient time after each procedure for V̇e to return to its prior steady-state level. The increment in V̇e after the hypercapnic hypoxia episode was used as an index of the peripheral chemoreflex CO2 contribution to exercise hyperpnea. Peak V̇e to hypercapnia was calculated by averaging the two to three breaths. The difference between peak V̇e to hypercapnia and steady-state V̇e during exercise was defined as ΔV̇ec. This test also leads to brief hypercapnic normoxia during submaximal exercise, as indicated by reference data for the hypercapnic normoxic condition. The slope of HCVR (L · min−1 · mm Hg−1) was also was also obtained by the same manipulation, that is, ΔV̇ec/ΔPetCO2.
Data are shown as means ± SEM. An analysis of variance with repeated measurement was used to analyze changes within each experiment. Post hoc Tukey's test for a significant F value was applied to specify where significant differences occurred. A probability level of less than 0.05 was accepted as significant.
Table 1 shows the characteristics of subjects who performed the incremental exercise test on a cycle ergometer under both hypoxic and normoxic conditions. V̇o2 in response to significant changes in the work rate was significantly lower at 12% O2 hypoxia (mean ± SEM: 15.3 ± 0.6 ml · kg−1 · min−1) than at normoxia (21.9 ± 0.7 ml · kg−1 · min−1). Higher work rates were obtained at normoxia (146 ± 7.7 W) than at hypoxia (97 ± 5.1 W).
Figure 1. Time course of end-tidal PCO2 (PETCO2), PO2 (PETO2), SaO2, and ventilatory responses (V̇E) to the abrupt inhalation of 100% O2 test and to hypercapnic (FICO2 = 10%) test for three breaths in condition of 80% VTh work rate of exercise under hypoxic and normoxic conditions for a typical subject. The shadow area indicates changes in the concentrations of inhaled O2 or CO2. The smoothing lines indicate that the decrease of V̇E in response to hyperoxia (A and B) and the increase of V̇E to hypercapnia (C and D) by a three-breath moving average of pulmonary breath-by-breath V̇E responses. The dotted line indicates the time course of SaO2.
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Figure 2. The transient change (in absolute units) from the steady state caused by the three breaths of O2 or CO2 (ΔV̇Eo, ΔV̇Ec) and the slope change expressed as ΔV̇Eo/ΔSaO2 and ΔV̇Ec/ΔPETCO2 as a function of work rates of exercise (40%, 60%, and 80% VTh). HRV (ΔV̇Eo, ΔV̇Ec/ΔSaO2) in A and HCVR (ΔV̇Ec, ΔV̇Ec/ΔPETCO2) in B are shown. Referenced data under normoxic conditions are positioned at right side. Data are shown as mean ± SEM. Significant difference among work rates at *p < 0.05, **p < 0.01. Significant difference from normoxia at †p < 0.05 and ††p < 0.01.
[More] [Minimize]Figures 1C and 1D illustrate the effects of CO2 breathing (FiCO2 = 10%) under hypoxic and normoxic conditions at 80% VTh, as examined in a typical subject. ΔV̇ec increased to 10.7 ± 1.2, 11.3 ± 1.1, 11.1 ± 1.6 L · min−1 at 40%, 60%, and 80% VTh in response to transient high-CO2 breathing, respectively, and to 8.3 ± 1.1 L · min−1 under normoxic conditions, with the increase reaching significance between 60%VTh and normoxia (seen in Figure 2B; p < 0.05). There was no discernible increment of ΔV̇ec among the different work rates at hypoxia, even though ΔV̇ec/ΔPetCO2 became significant in a comparison between 40% VTh and 60% VTh during hypoxia and between 40% VTh and normoxia. As a consequence, the peak V̇e during the hypercapnic hypoxic test was 39.2 ± 2.5, 45.5 ± 3.0, 53.8 ± 2.8 L · min−1 at 40%, 60%, and 80% of VTh, respectively, and 35.3 ± 2.5 L · min−1 under normoxic conditions.
Steady-state values of V̇e, V̇o2, and V̇co2 under hypoxic conditions increased proportionally with the increase in work rates from 40% to 80% VTh. At 80% VTh, there were significantly higher V̇o2, V̇co2, and V̇e values at hypoxia than at normoxia, despite there being the same absolute work rate. Hypoxia was also associated with a lower PetCO2, averaging 37.5 to 38.7 mm Hg, and a lower PetO2, averaging 49.3 to 50.3 mm Hg (Table 2)
40% VTh | 60% VTh | 80% VTh | Normoxia | |
|---|---|---|---|---|
| V̇E, L min−1 | 28.7 ± 1.4 | 34.2 ± 1.9 | 42.5 ± 1.4 | 27.2 ± 1.5 |
| V̇O2, ml min−1 | 668 ± 35 | 879 ± 27 | 1,080 ± 32 | 1,025 ± 29 |
| V̇CO2, ml min−1 | 627 ± 36 | 866 ± 41 | 1,050 ± 45 | 839 ± 43 |
| PETCO2, mm Hg | 38.7 ± 0.5 | 38.5 ± 0.7 | 37.5 ± 0.7 | 40.5 ± 0.9 |
| PETO2, mm Hg | 50.0 ± 1.0 | 49.3 ± 1.3 | 50.3 ± 1.0 | 100.3 ± 1.3 |
| SaO2, % | 83.5 ± 1.5 | 81.2 ± 1.7 | 80.5 ± 1.1 | 94.5 ± 0.5 |
| Work rate, W | 39 ± 2.0 | 58 ± 3.1 | 78 ± 4.1 |
The computer-derived line of best fit to a monoexponential function of time-averaged responses of V̇o2, V̇co2, and V̇e is shown in Figure 3
Figure 3. Mean responses of (A) O2 uptake (V̇O2), (B) CO2 output (V̇CO2), and (C) V̇E to 80% VTh work rate of exercise for all subjects during FIO2 = 0.12. Values shown are ensemble-averaged 5-second interpolated data from two repetitions by all subjects ± SEM. The solid line is the best-fit responses at 80% VTh work rate of exercise. The vertical lines indicate onset of work rate (i.e., on-kinetics, left panels) and cessation of the work (i.e., off-kinetics, right panels).
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Figure 4. t1/2s on V̇O2, V̇CO2, and V̇E kinetics at on-transient phase of work (filled bar) and at off-transient phase (open bar) as a function of work rates of exercise. Reference data of variable kinetics at FIO2 = 0.21 are indicated on the right side. Significant difference from 80% VTh work rate at *p < 0.05, **p < 0.01. Significant difference from normoxia at †p < 0.05, ††p < 0.01.
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Figure 5. Mean response of V̇O2 to 80% VTh work rate of exercise for all subjects during FIO2 = 0.12. Values shown are ensemble-averaged 5-second interpolated data from two repetitions by all subjects ± SEM. Solid lines show best-fit responses at 80% VTh work rate of exercise. Vertical lines indicate onset of work rate (i.e., on-kinetics, left panels) and cessation of the work (i.e., off-kinetics, right panels).
[More] [Minimize]The shortened t1/2 V̇e on-kinetics was related to the greater ΔV̇eo/ΔSaO2 and reached a level of significance (r2 = 0.709, p < 0.001). In addition, we were able to check the contributing weighted factors of HVR (ΔV̇eo/ΔSaO2) and HCVR (ΔV̇ec/ΔPetCO2) using multiregression analysis, independent of exercise hyperpnea, under hypoxic condition.
The multiregression line can be described as follows:
 |
Thus, t1/2 V̇e has a convincing relation to the chemoreflex drive responding to O2 and CO2 (r2 = 0.721), suggesting that the chemoreflex drive can account for more than 72% of ventilatory dynamics. Based on the results, r2 and the standardized regression coefficients were 0.742 in HVR and −0.105 in HCVR; t1/2 V̇e was immovably reflected by the chemoreflex O2 drive rather than by the chemoreflex CO2 drive. In the results, HVR accounted for 63.2% (0.721 · 0.742 · 100/[0.742 + 0.105]) and HCVR for 8.9% in response to exercise hyperpnea (i.e., t1/2 V̇e) at the onset of exercise. Therefore, unidentified physiologic factors were occupied as the ratio of 27.9%.
We observed that the chemoreflex drive to isocapanic hypoxia, that is, HVR, is enhanced with an increase in the work rate of moderate exercise under hypoxic conditions, whereas the chemoreflex drive to hypercapnic hypoxia, that is, HCVR, does not change with different work rates during constant exercise. Apparently, the chemoreflex drive to both O2 and CO2 under hypoxic conditions is significantly larger than under normoxic conditions. Altered work rates affect carotid-body activity, thus resulting in greater HVR during steady-state exercise. Gas-exchange dynamics at the onset of exercise demonstrated that although t1/2 V̇o2 on-kinetics are unaffected by alternating the work rate, much faster V̇e and V̇co2 dynamics at hypoxia are proportional to increases in the work rate. As a consequence, the new findings show that the chemoreflex O2 drive rather than the chemoreflex CO2 drive contributes to hypoxic-exercise hyperpnea (i.e., t1/2 V̇e) at the onset of exercise.
The carotid bodies represent the primary site of HVR as peripheral chemoreflex responsiveness involving manipulation of the inhaled O2 fraction in humans (1) and in patients with carotid-body resection (25, 26). As shown in Figure 2, in this study, the ΔV̇eo/ΔSaO2 using the O2 test under hypoxic conditions was −0.230, −0.447, and −0.728 L · min−1 · % −1, respectively, on average, proportional to increases in the work rate. It has previously been observed that the augmented chemoreflex drive via the carotid body can be seen in denervated cats with increased sympathetic nervous activity (27) and in response to the infusion of norepinephrine (28), with the effects being similar to those that we have observed in exercise.
Hypoxia is a potent vasodilator and thus would result in a greater increase in blood flow via the carotid body. Therefore, an increase in blood flow during hypoxia may improve the equilibration of CO2 in different compartments. According to this physiologic explanation, HCVR could be augmented with an increase in the work rate during hypoxic exercise; in this study, however, the ΔV̇ec and ΔV̇ec/ΔPetCO2 were unaffected by changes in the work rates at hypoxia (Figure 2), a finding that is in agreement with previous results (4). Our finding demonstrates that CO2 responsiveness via most peripheral chemoreceptors is unaltered by increases in sympathetic activation and carotid-body blood flow, whereas it is significantly increased compared with normoxia. In another point regarding CO2 responsiveness via the carotid body, some studies using the CO2-flow method have demonstrated a large increase in CO2 sensitivity in terms of the operating point during light or moderate exercise (6–9), whereas others using the CO2 flow or rebreathing method have found that the sensitivity is unaffected by exercise (10–13). Taken together, these results lead us to suspect that CO2 sensitivity during exercise is particularly affected by the CO2-inhalation methods used experimentally.
In this study, the V̇e dynamics in response to exercise at hypoxia not only increased with increases in the work rate but also exceeded those at normoxic conditions (Figure 4). The carotid bodies are considered the primary mediators of dynamics at the transient phase in response to increases in work rate (2, 29). Previous studies have shown that under conditions of increased carotid-body gain such as induced hypoxia, V̇e dynamics are accelerated (1, 15, 30). Conversely, reduced carotid-body gain in response to induced hyperoxia (1, 15, 30) or carotid-body resection (25) results in slowed V̇e dynamics. Even though the faster V̇e dynamics with increases in work rates suggest that the carotid-body gain in response to O2 is affected by work rates, this effect cannot be discriminated from the possible effects of the somewhat faster V̇co2 response. Regarding drug ingestion that functionally inhibits the transport of CO2 from active tissues to the lung, acute acetazolamide administration has been found to abolish effectively the ventilatory response to hyperoxia and reduce the ventilatory response to hypoxia caused by reduced drive from the peripheral chemoreflex (31). The lowering of body CO2 stores before main exercise may in part explain the slower V̇co2 dynamics and, subsequently, the slower V̇e dynamics (32).
However, the effective interaction between V̇co2 and V̇e cannot be supported by our results at 60% and 80% VTh under hypoxic conditions; we show the ratios of t1/2 V̇e to t1/2 V̇co2 calculated from mean values in Figure 4 are 1.04, 0.95, and 0.97 at 40%, 60%, and 80% VTh, respectively, suggesting that V̇e dynamics are faster than V̇co2 dynamics at 60% VTh and 80% VTh during hypoxia. These findings agree with data in other reports (1). It seems likely that a strong linkage of V̇co2 and V̇e dynamics at the onset of exercise at moderate work rates (32–34) was not established under hypoxic conditions in this study; thus, the preceding V̇e was likely caused by the strong peripheral chemoreceptor drive at hypoxia, by which the increased sympathetic nervous activation and blood flow into the carotid body might produce in response to increases work rate, but not in CO2 flow.
Even though t1/2 V̇e was found to be convincingly related to the chemoreflex drive (r2 = 0.721), suggesting that the chemoreflex drive can account for more than 70% of the ongoing ventilatory dynamics in response to exercise under normocapnic hypoxic conditions, it is necessary to consider what accounts for the remaining 28%. The hypoxic ventilation–exercise interaction is mediated by the activation of chemosensitive afferent nerve endings within active muscles, otherwise known as “muscle chemoreceptors” (35), and this effect is potentiated by hypoxia (36). Chemoreceptors within exercising muscles would be stimulated more during hypoxic than during normoxic exercise, leading to increased afferent input to the respiratory center and an increase in ventilatory output (37). According to an alternative hypothesis proposed by Masson and Lahiri (38), the augmentation of hypoxic ventilation during exercise seems to occur without any increase in the activity of peripheral chemoreceptors. Based on this study, it is possible that only a fixed threshold level of chemoreceptor afferent input is required to cause the hypoxic ventilation–exercise interaction. In this scheme, unknown factors accompanying exercise may increase the excitatory state of central respiratory neurons so that more of them are close to the firing threshold. Any level of incoming chemoreceptor input would therefore be more effective at depolarizing these cells, leading to increased central respiratory drive and ventilatory activity. Considering the respiratory central mechanism, Eldridge (39) has emphasized the slow respiratory central neural dynamics in the cat based on a demonstration of relatively slower ventilatory kinetics, which may account in part for the slowed off-transient effects in humans. In addition, the parallel drives in both ventilation and locomotion can be mediated by a hypothalamic mechanism (39). However, although these hypotheses remain acceptable, we do not know of any experimental data to either support or refute the concept of muscle-chemoreceptor and respiratory central command in humans.
Previous studies have shown that under conditions of increased carotid-body gain such as induced metabolic acidosis (40) and hypoxia (1, 15, 30), V̇e dynamics are faster. Conversely, reducing carotid-body gain by induced metabolic alkalosis (41), hyperoxia (1, 15, 30), or carotid-body resection (2) results in slowed V̇e dynamics. Pianosi and Marchione (42) have found an inverse relationship between ΔV̇e to O2 and the degree of exercise hyperventilation (r2 = 0.469), which is mostly consistent with our present observations. The carotid-body contribution to breathing is appreciably greater during the steady state of moderate exercise than during rest (5, 13, 43); additionally, there has been a very interesting report that greater HVR and HCVR via chemoreceptors is closely related to the more intense breathlessness, which accounts for 70% of the sensation of breathlessness (44). The chemoreflex drive occurring mostly via the carotid body contributes to the hypoxic–ventilatory response at both the steady state and the onset of exercise and, concomitantly, to the breathless sensation during exercise.
Although V̇o2 dynamics are unaffected by alterations in the work rate under hypoxic conditions, hypoxia results in slower V̇o2 dynamics; ultimately, however, the same steady-state V̇o2 can be achieved (19, 45). In concert with the slower V̇o2 dynamics seen under hypoxic conditions, the O2 deficit is greater than under normoxic conditions (18), implying a greater reliance on anaerobic sources of high-energy phosphates. Engelen and colleagues (46) have observed that moderate hypoxia results in slowing of V̇o2 dynamics with moderate-intensity exercise, and during heavy exercise performed under hypoxic conditions, a similar pattern of V̇o2 response has been found for the primary transient component. Indeed, the slower V̇o2 dynamics occurring at hypoxia are associated with a greater reduction in muscle high-energy phosphates and a greater rise in blood flow and muscle lactate concentrations, with the latter likely being inversely related to the inhaled O2 fraction.
This study has identified the changes in HVR or HCVR occurring with increases in the work rate, and the very strong relationship between hypoxic–exercise ventilatory dynamics and HVC or HCVR, which can account for more than 70% of the ongoing ventilatory dynamics in response to exercise. Augmented HRV and unaltered HCVR were observed with increasing work rates at hypoxia, clearly demonstrating that the augmented chemosensitivity to exercise arises in the carotid body, which depends on an increase in mechanical work rates. As a result, a number of potential factors may be involved, including increased sympathetic nervous activity and blood flow via the carotid body and increased norepinephrine levels. Concomitantly, the t1/2 of V̇e on-kinetics are significantly lower at hypoxia than at normoxia, depending on the changes in inspired O2 concentrations. The work-rate–dependent augmentation in peripheral chemoreceptor drive, that is, HRV, which may be humorally and/or neurally mediated by the flux of afferent neural activity, is the primary contributor to the regulation of hypoxic–exercise hyperpnea during the transient phase of exercise. Otherwise, V̇o2 dynamics are merely affected by the lower O2 levels but independent of the changing work rates under hypoxic conditions.
The authors thank Drs. Mitsuharu Inaki and Nobuharu Fujii and Kei Sakamoto, University of Tsukuba, Japan, for technical assistance.
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