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1 Canadian Centre for Activity and Ageing2 School of Kinesiology3 Department of Physiology and Pharmacology, The University of Western Ontario, London, Ontario N6A 3K7, Canada 4 Countess of Chester Hospital, Liverpool Road, Chester CH2 1UL, UK
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Abstract |
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increased to 40.3 ± 4.5% of the initial hypoxic ventilatory response, and by 36 min
increased to 100%, indicating that peripheral chemosensitivity to hypoxia was restored. The
response magnitude plotted versus time demonstrated that
, hence peripheral chemosensitivity, was restored at a rate of 1.9% per minute. Cerebral blood flow (CBF, inferred from CBV) remained constant during sustained hypoxia and increased by the same magnitude during the hypoxic pulses, suggesting that CBF has a small, if any, impact on the decline in
during hypoxia and its subsequent recovery. To address the issue of whether hypoxic pulses affect subsequent challenges, series (continuous hypoxic pulses at various recovery intervals) and parallel (only 1 pulse per trial) methods were used. There were no differences in the ventilatory responses between the series and parallel methods. Older adults demonstrated a similar rate of recovery as in the young, suggesting that ageing in active older adults does not affect the peripheral chemoreceptor response.
(Received 7 March 2004;
accepted after revision 14 July 2004; first published online 15 July 2004)
Corresponding author Donald H. Paterson, Canadian Centre for Activity and Ageing, 1490 Richmond Street, London, Ontario, Canada, N6G 2M3. Email: dpaterso{at}uwo.ca
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Introduction |
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increases within the first few minutes and then declines over the next 10–15 min (known as hypoxic ventilatory decline, HVD) to a new plateau. The cause of HVD has been investigated. Since hypoxia serves as a potent vasodilator, it is possible that the increase in cerebral blood flow to the medulla may wash out CO2 surrounding the respiratory centres, thereby reducing the CO2 drive and resulting in a decline in 
. However, transcranial Doppler indices of cerebral blood flow (CBF) have excluded this as a cause for HVD (Poulin & Robbins, 1998), suggesting that the cause is due to other factors. Peripheral chemoreceptors in the carotid bodies appear to be the key factor in the HVD response. Modelling of the ventilatory response to sustained hypoxia has demonstrated that the fast on- and off-responses, representing peripheral chemoreceptor drive, are asymmetrical (Easton et al. 1986; Khamnei & Robbins, 1990), and suggests that peripheral chemosensitivity may decrease during the course of sustained hypoxia, resulting in different on- and off-responses. Although it has been argued that in anaesthetized animals signals from the carotid bodies are modified in the brain by inhibitory neurotransmitters such as GABA during HVD (Tabata et al. 2001), it is believed that in conscious humans sustained hypoxia decreases peripheral chemosensitivity through physical changes in the carotid bodies (Bascom et al. 1990).
Bascom et al. (1990) assessed peripheral chemosensitivity during sustained hypoxia in humans by introducing a series of brief 1.5 min hypoxic pulses at an end-tidal partial pressure of oxygen (PO2) of 45 mmHg during a period of sustained hypoxia at 50 mmHg and compared the magnitudes of the increase in 
with the assumption that the degree of increase is indicative of peripheral chemosensitivity. Based on their findings, the hypoxic ventilatory response, hence peripheral chemosensitivity, decreased at a rate of 4.2% per minute and plateaued after approximately 15 min.
The depressant effects of hypoxia on peripheral chemosensitivity persist for some time after re-institution to euoxia; however, it is unclear whether the rate and duration of peripheral chemoreceptor resensitization matches that of desensitization. Easton et al. (1988) tested the recovery of ventilatory responses following 20 min of hypoxia with hypoxic pulses at 15, 30 or 60 min and found that peripheral chemosensitivity was restored by 60 min of room air breathing. Khamnei (1989), using a similar protocol to Bascom et al. (1990), reintroduced a series of brief hypoxic pulses during euoxic recovery following a period of sustained hypoxia and measured the hypoxic ventilatory response. Khamnei & Robbins (1990) reported that peripheral chemosensitivity was restored after approximately 40 min of room air breathing. In this study, however, the hypoxic pulses were given in series at successive times throughout recovery. It is not known whether these hypoxic pulses may have added to the depressant effects of hypoxia, thereby prolonging resensitization of the peripheral chemoreceptors.
The impact of reduced peripheral chemosensitivity on the rate and duration of peripheral resensitization following sustained hypoxia is also unknown. A commonly studied group are older adults (>70 years old) because they have been reported to have a decreased peripheral chemoreceptor response to hypoxia (Kronenberg & Drage, 1973; Peterson et al. 1981; Poulin et al. 1997). In a recent report from our laboratory, however, the ventilatory responses during sustained hypoxia were similar between young and physically active older adults, suggesting no change in peripheral chemosensitivity with age (Smith et al. 2001). The ventilatory recovery from sustained hypoxia has not been studied in older adults. Assuming that ventilatory recovery from hypoxia is dependent upon peripheral chemosensitivity, it would be expected that older adults with reduced peripheral chemosensitivity would demonstrate a slower rate and longer duration of recovery compared to younger adults.
The purpose of the first part of this study was to characterize the peripheral chemoreflex control of 
by defining the rate and duration of peripheral resensitization following 20 min of sustained hypoxia in young adults (group 1). Although increases in CBF during sustained hypoxia do not cause the decline in 
, CBF (inferred from velocity measurements) was determined to ensure that CBF did not influence the ventilatory response to hypoxia post-HVD. In the second part of the study, young (group 2) and older subjects (group 3) were compared to determine whether a decrease in peripheral chemosensitivity due to ageing had an effect on the rate of peripheral chemoreceptor resensitization. Two methods (series and parallel) were employed in both young and older adults to determine whether a series of hypoxic pulses prolonged recovery. It was hypothesized that: (1) peripheral resensitization would take longer and occur at a slower rate compared to desensitization; (2) cerebral blood flow during recovery would not affect the hypoxic ventilatory responses; (3) physically active older adults would show a similar rate of recovery to young adults following HVD; and (4) the method of assessment (the imposition of hypoxic pulses in series versus single pulses at different time points (parallel)) would have no impact on recovery.
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Methods |
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The study was performed according to the Declaration of Helsinki. After the committee for human experimentation at the University of Western Ontario approved the protocol, three groups, each comprising five subjects, gave their informed written consent to participate in the study. Group 1 consisted of three young men and two women (25 ± 3 years old), group 2 of five young males (30 ± 8 years old) and group 3 of five older males (74 ± 3 years old). The female subjects were tested during the early follicular phase to avoid the confounding effects of progesterone. Group 1 participated in protocol A, while groups 2 and 3 participated in protocol B (Fig. 1). The experimental design of both protocols and potential discomforts were explained to the subjects before testing. Although the subjects were not physically examined, their medical history indicated that they were nonsmokers with no known cardiorespiratory problems, and that they took part in some form of regular physical activity but were not involved in athletic training. The subjects were asked to refrain from strenuous exercise for at least 4 h before testing.
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Subjects sat quietly in a chair and breathed though a mouthpiece with the nose occluded. End-tidal PO2 (PET,O2) and end-tidal partial pressure of CO2 (PET,CO2) were clamped using a steady-state technique. This technique involves breath-by-breath gas analysis with computer-controlled end-tidal forcings designed to clamp PET,O2 and PET,CO2 at desired levels. As previously described (Poulin et al. 1997), respiratory volumes were measured by a turbine and volume transducer (Sensormedics VMM-2 A). Respiratory flows and timing information of the beginning and end of each inspiration and expiration were obtained using a pneumotachograph (Hans Rudolf Inc., Model 3800) and a differential pressure transducer (Validyne Mp45-871). Gas was sampled at the mouth at the rate of 20 ml min–1 and analysed by a mass spectrometer (Perkin-Elmer MGA-1100) for fractional concentrations of O2, CO2 and N2. Two computers were used: one functioned as the data acquisition computer and the other served as the control computer. The data acquisition computer collected the experimental variables every 20 ms from the mass spectrometer, turbine inspiratory and expiratory channels, pneumotachograph and electrocardiogram and stored the data for future analysis. The control computer measured CO2 and O2 at the end of each breath and added sufficient CO2 and O2 for the next breath to maintain the clamp at the desired level.
In an upright, seated position, heart rate was measured by standard ECG methods. Mean cerebral blood velocity (CBV) in the middle cerebral artery (MCA) was measured using a 2 MHz pulsed transcranial Doppler ultrasound system (TCD) in group 1.
Protocol
The level of isocapnia used in the present study was set at 1.5 mmHg CO2 above resting PET,CO2. To obtain resting PET,CO2 values, subjects breathed humidified air for 5 min. The average PET,CO2 of the last 10 breaths was taken as resting PET,CO2. This was done for each subject and repeated before each experimental trial.
End-tidal PO2 was initially clamped at euoxic levels (100 mmHg) for 10 min, followed by 20 min at hypoxic levels (50 mmHg). Hypoxia was re-introduced for brief periods lasting 1.5 min at intervals described below and shown in Fig. 1. Both protocols were repeated three times in each individual. Each trial was separated by at least 24 h to avoid any potential residual physiological effects of sustained hypoxia.
Protocol A: ventilation recovery and cerebral blood flow. Additional hypoxic pulses were introduced at 5, 11, 17, 23, 29, 35 and 41 min following 20 min of sustained hypoxia in group 1 (Fig. 1A). Cerebral blood velocity was measured to determine potential effects of increased blood flow on the ventilatory response to the hypoxic pulses.
Protocol B: method and age.
Two techniques of assessing peripheral chemosensitivity in young (group 2) and older adults (group 3) were used to determine whether a series of hypoxic pulses prolonged resensitization of the peripheral chemoreceptors. With the series method, hypoxic pulses were re-introduced at 2, 8, 14 and 20 min following 20 min of sustained hypoxia (Fig. 1B). These data were combined with those obtained from protocol A to increase the number of data points describing rate and duration of peripheral chemoreceptor resensitization. With the parallel method, only 
responses associated with the first pulse in each set shown in Fig. 1B were used, thus eliminating any potential confounding effects of previous hypoxic pulses on 
. If the number of pulses in protocol B were to extend to 41 min post-HVD as in protocol A, at least 27 experimental sessions would be required by the subject (one for each of the 7 hypoxic pulses plus two repeats). Since this may have been tiresome for the subjects, particularly the older group, protocol B was extended to only 20 min. We thought that this was enough time to determine whether there were differences in method (series versus parallel) and age (young versus old).
Analysis
Breath-by-breath changes in 
were overlaid for each subject to reduce noise and averaged into 5 s bins. The magnitudes of the ventilatory response to hypoxia were calculated by subtracting the peak amplitude with the previous baseline value. The ventilatory response to the hypoxic pulses was normalized by expressing it as a percentage of the initial ventilatory response to sustained hypoxia. The initial ventilatory response was determined by averaging 
within the first 2 min of the hypoxic step. This time period contains the peak ventilatory response before 
begins to decline (Smith et al. 2001). Normalized 
values from each subject were ensemble averaged and plotted as a function of time. For protocol A, a one-way repeated measure of analysis of variance was used to compare the normalized 
magnitudes during the hypoxic pulses to that from the initial ventilatory response. When variation was detected, a multiple comparison (Tukey's method) was used and differences between means with a P value of 0.05 or less were considered significant. For protocol B, a two-way repeated measure of analysis of variance was used to compare the normalized 
magnitudes between methods (series versus parallel) and age (young versus old). The normalized 
magnitudes from protocols A and B were plotted over time, and in the case of protocol A, a linear regression equation was applied to the data to determine the rate and time for full ventilatory recovery following HVD. Using a linear regression was the simplest method to fit the data from the present study and the data from previous studies that have fewer data points, which makes other forms of fitting difficult (i.e. exponential). Furthermore, using the same method to fit the data from previous studies allows for comparisons to be made to the data from the present study.
The spectra of the TCD signal were used to determine CBV in the MCA. Beat-by-beat mean CBV was calculated as the average of the instantaneous CBV values over each cardiac cycle using the QRS complex of the electrocardiogram tracing to signal the end of one blood pulse wave and the beginning of the next pulse wave. The beat-by-beat CBV data for the repeated trials were time aligned and averaged over 10 s time bins. We used the last 10 s of each 90 s pulse of hypoxia to determine CBV since it offers a more accurate representation of steady-state CBV (Poulin et al. 1996). Using the entire period would underestimate the actual CBV response. The calculated amplitudes of the CBV response to the hypoxic pulses were compared in the same manner as 
described above.
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Results |
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A sample raw tracing of the ventilatory and CBV responses in the MCA in one representative subject following protocol A is illustrated in Fig. 2. The normalized ventilatory response during the first hypoxic pulse in protocol A (i.e. 5 min following the relief from sustained hypoxia) was significantly depressed, increasing to only 40.3 ± 4.5% of the initial hypoxic ventilatory response. The ventilatory response to subsequent hypoxic pulses progressively increased with subsequent bouts of hypoxia until 35 min, at which time the hypoxic ventilatory response was the same as the initial response, indicating that peripheral chemosensitivity was completely restored (Fig. 3). The data points from protocols A and B were combined. A linear regression of these data demonstrated a similar recovery time for both protocols at 36 min, at a rate of 1.9% increase in 
per minute or 0.4 l min–2 following sustained hypoxia (Fig. 4, closed circles). Since the magnitude by which 
increases is indicative of peripheral chemosensitivity, Fig. 4 also describes the rate and duration of peripheral chemoreceptor resensitization. The data from Bascom et al. (1990) were adapted and included in this figure (open circles) to illustrate the difference in the rate of peripheral chemoreflex desensitization (Bascom et al. 1990) compared to resensitization (present study). The hypoxic pulses used in Bascom's study (1990) were at a lower PET,O2 (45 mmHg) compared to the present study (50 mmHg). However, since the magnitude of the 
response is an indication of peripheral chemosensitivity, it serves as a good indicator of the rate of peripheral chemoreceptor desensitization.
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Despite changes in 
, CBV response during sustained hypoxia remained constant (Table 1). The change in magnitude of CBV during each hypoxic pulse was normalized to the initial CBV response, similar to 
(Fig. 5). There were no significant differences in CBV during the recovery period compared to the sustained hypoxic period.
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The magnitude of the ventilatory responses to the hypoxic pulses, normalized by expression as a percentage of the initial ventilatory response to hypoxia (i.e. 100%), for the series and parallel data is shown in Fig. 6 for groups 2 (young) and 3 (old). The ventilatory responses between the series and parallel data were the same for each pulse, indicating that the series method does not prolong the depressive effects of hypoxia. However, the ventilatory responses during all four hypoxic pulses were significantly less than the initial hypoxic ventilatory response, or 100%, suggesting that peripheral chemosensitivity was still blunted.
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Although resting PET,CO2 was lower for the older subjects (33.4 ± 1.8 mmHg) than for the young subjects (36.8 ± 1.5 mmHg, P > 0.05), clamp levels of PET,CO2 (resting PET,CO2 +1.5 mmHg) and PET,O2 were not different between the young and older subjects (Table 2). Comparison of the ventilatory responses between the young and older subjects demonstrated no significant differences, indicating that ageing in active older adults does not affect the rate of peripheral chemoreceptor resensitization and that hypoxia has the same effect on peripheral chemosensitivity (Table 2 and Fig. 6).
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Discussion |
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Peripheral chemosensitivity
Although the role of the peripheral chemoreceptor is critical for the development of HVD, such that removing the carotid bodies (Kimura et al. 1998) or inhibiting their function with dopamine (Dahan et al. 1996) abolishes HVD, its role as the cause of HVD is debatable. Currently, there are two schools of thought. In the unconscious or anaesthetized state, the development of HVD is independent of the peripheral chemoreflex and is dependent on central mechanisms. The mechanism may involve central inhibition of the respiratory centres in the medulla without affecting peripheral chemoreflex sensitivity. For example, in the anaesthetized cat, isolated perfusion of the brainstem with hypoxaemic blood decreased 
(Van Beek et al. 1984), while selective perfusion of the carotid bodies failed to induce HVD (Daristotle et al. 1991). Furthermore, carotid sinus nerve activity increases during HVD in anaesthetized rats (Vizek et al. 1987) despite a decrease in phrenic nerve activity (Milhorn et al. 1984).
In the conscious state, however, HVD appears to be the result of another mechanism involving progressive reduction of peripheral chemosensitivity. In both humans (Easton et al. 1986; Khamnei & Robbins, 1990) and animals (Long et al. 1994), modelling the 
response to a steady-state decrease in PET,O2 demonstrated a rapid decline in 
(off-response) upon removal of the hypoxic stimulus that was slower than the rapid rise in 
(on-response). Since rapid changes in 
are due to the peripheral chemoreflex (Khamnei & Robbins, 1990), these data suggest a reduction in peripheral chemosensitivity. The mechanism by which peripheral chemosensitivity decreases during sustained hypoxia appears to be different in humans compared with other animals. In cats, carotid sinus nerve traffic to the respiratory centre is diminished by central inhibitory neurotransmitters such as 
-aminobutyric acid (GABA; Tabata et al. 2001), glutamate (Hoop et al. 1991) and taurine (Burton & Kazemi, 2000), suggesting that it is modulated centrally; however, this does not appear to be the case in humans (Nagyova et al. 1993). During HVD, the ventilatory response due to peripheral chemoreflex input is reduced more in response to hypoxic than hypercapnic stimuli (Bascom et al. 1990) and, assuming that the peripheral chemoreflex response to hypoxia and hypercapnia is encoded in the same nerve fibres (Lahiri & DeLaney, 1975), these data suggest that peripheral chemosensitivity is modulated peripherally in the carotid bodies. Some of the conflicting reports from studies in humans, however, may be due to natural variations in human subjects themselves. Liang et al. (1997) reported that in some awake humans (2 of 6 subjects) a component of HVD may be independent of the peripheral chemoreflex. Although the present study did not investigate this possibility, it is assumed that by testing conscious humans, the HVD in most if not all subjects was due to a reduction in peripheral chemosensitivity. Furthermore, assuming that the cause of HVD is also responsible for its gradual recovery, the ventilatory response to acute bouts of hypoxia during recovery following sustained hypoxia represents a resensitization of the peripheral chemoreflex.
In their study of HVD, Bascom et al. (1990) administered additional 1.5 min hypoxic pulses during a 20 min sustained hypoxic period to determine the rate at which peripheral chemosensitivity decreased. They reasoned that the magnitude of 
increase due to the hypoxic pulses was indicative of peripheral chemosensitivity. Based on their findings, peripheral chemosensitivity decreased from 131.7 ± 12.9% at 2 min to 65.3 ± 15.8% at 17 min within the sustained hypoxic period, indicating a decrease of 4.2% per minute (Fig. 5). Interestingly, the rate of peripheral chemosensitivity recovery in the present study did not mirror this rate of decline. In the present study, the hypoxic ventilatory response post-HVD increased by 1.9% per minute, a rate that is approximately two times slower than its decline. Given that the capacity of the peripheral chemoreflex to respond to stimuli such as hypoxia is reduced, it would be expected that the response to additional hypoxic stimulation post-HVD would be blunted, resulting in a slower rate of resensitization compared to desensitization (Bascom et al. 1990). It may be argued that peripheral chemosensitivity declined at a faster rate in the study of Bascom et al. (1990) because they used hypoxic pulses at a PET,O2 of 45 mmHg, whereas the present study used 50 mmHg. However, in both studies, only the change in magnitude of 
was measured. Furthermore, these magnitudes were normalized, thus allowing direct comparisons to be made.
The mechanism for the slower rate of peripheral chemoreflex resensitization will be better understood once the path by which hypoxia stimulates the chemosensitive cells in the carotid bodies is determined. Desensitization of the peripheral chemoreceptors during sustained hypoxia may involve cellular alterations in the glomus cells of the carotid bodies (Bissonnette, 2002) and so resetting them may involve changes that return these chemosensitive cells back to their original state. In addition, restoration of peripheral chemosensitivity appears to be O2 dependent, such that recovery is hastened with the administration of hyperoxic air, requiring as little as 7 min for full recovery (Easton et al. 1988). Therefore, the rate of peripheral chemoreflex recovery may require cellular changes that are both time and O2 dependent.
Interestingly, sustained hypoxia also produces a persisting elevation in muscle sympathetic activity (MSNA) that requires up to 40 min to return to baseline values (Xie et al. 2001), a similar time course to peripheral resensitization reported in the present study. Several studies have shown a relationship between chemosensitivity and sympathetic activity. For instance, patients with sleep apnoea exhibit an enhanced peripheral chemosensitivity and hypertension due to elevated sympathetic activity (Narkiewicz et al. 1999). Although it is unclear how an elevated MSNA following sustained hypoxia impacts the rate of peripheral resensitization, if at all, it does suggest a link between peripheral chemosensitivity and sympathetic activity.
The persisting blunted peripheral chemoreflex control of 
during and following sustained hypoxic stimulation is important for understanding and treating certain abnormal conditions, such as respiratory arrest associated with disorders like sleep apnoea. Although respiratory diseases and disorders are often associated with other complications, such as cardiovascular insufficiencies, these data provide some insight into the role of peripheral chemoreceptors. These results may also prove useful to those who are studying the effects of sustained hypoxia on 
. For those wishing either to capture the lasting effects of HVD or to avoid these effects, this study provides a precise time frame to follow.
Cerebral blood flow
The relationship between CBF and 
has been of some interest to investigators studying the mechanism of HVD. It has been postulated that HVD may be due at least in part to increases in CBF (due to the vasodilatatory effects of hypoxia), which wash out CO2 resulting in alkalosis and a reduction in central chemoreceptor activation of 
(Ellingsen et al. 1987). Furthermore, lactic acid, adenosine and other metabolites of anaerobic metabolism increase in the brain during conditions of hypoxia (Burton & Kazemi, 2000), and can also increase CBF. Although the central chemoreflex does not respond to hypoxemia, it is activated during isocapnia (Rapanos & Duffin, 1997), and attenuating its activity by reducing tissue PCO2 may contribute to the decline in 
(Nishimura et al. 1987). In agreement with previous reports in humans (Fukuda et al. 1989; Poulin et al. 1996), the present study demonstrated an increase in CBF during hypoxia that remained constant throughout the test, suggesting that central chemoreceptor stimulation is constant and is therefore not contributing to HVD. Furthermore, these data suggest that changes in brain metabolism due to hypoxia at 50 mmHg produce negligible affects on CBF.
Interestingly, comparison of the 
and CBF responses during the sustained and acute hypoxic periods demonstrated an uncoupling of the 
and CBF responses. While 
decreased and then increased during sustained and acute episodes of hypoxia, respectively, the increase in CBF was constant during all hypoxic manoeuvres. Therefore, changes in ventilatory control during hypoxic stimulation due to alterations in peripheral chemosensitivity had no impact on CBF.
Technical limitations
It is conceivable that the rapid pulses of hypoxia in series used in protocol A prolonged the ventilatory recovery by further contributing to the depressant effects of hypoxia on peripheral chemosensitivity. For example, Easton et al. (1988) separated two 20 min periods of hypoxia with 15, 30 or 60 min of euoxic breathing (parallel method), while Khamnei (1989) followed a single 20 min bout of hypoxia with brief, 1.5 min hypoxic pulses at 2, 8.5, 15 and 30 min post-HVD in a single test (series method). Given that 
begins to decline within 2–3 min after the onset of hypoxia, it is possible that repeated exposure to hypoxia post-HVD in series could prolong the recovery process. From the data of Khamnei (1989), recovery appears to have taken longer compared to the results of Easton et al. (1988). However, the results of the present study demonstrated a similar rate of recovery using both methods, which proves that hypoxic pulses in series did not propagate the depressant effects of hypoxia on peripheral chemosensitivity.
Cerebral blood flow is the product of CBV and vessel cross-sectional area and is assumed to be proportional to CBV provided that vessel diameter does not change. In the present study, we inferred CBF changes based on CBV measurements because our equipment was not capable of measuring vessel diameter. Using a similar end-tidal forcing technique, Poulin & Robbins (1998) found no change in vessel diameter during 20 min of isocapnic hypoxia, which supports the assumption that CBV can be used to reflect CBF in the present study.
Age
In untrained men over 70 years of age, ventilatory sensitivity to hypoxia is reduced (Poulin et al. 1997), resulting in a lower initial increase in 
in response to acute hypoxia (Kronenberg & Drage, 1973; Peterson et al. 1981). In a recent paper, Smith et al. (2001) reported that the ventilatory response to sustained hypoxia and its subsequent decline in active men over 70 years of age was the same as in their younger counterparts. In support of their findings, Ahmed et al. (1991) also found no differences in 
in response to 25 min of hypoxia in men aged 62 years. Using the same subject pool as that of Smith et al. (2001), the present paper also reports no difference in the ventilatory response to and its recovery from sustained hypoxia between the active older and young groups. Therefore, peripheral chemosensitivity remains intact in older adults who are physically active, and presumably a decrease in peripheral chemosensitivity in untrained older adults would result in a slower recovery from HVD.
Conclusions
This study characterized the peripheral chemoreflex control of 
during hypoxia following a period of sustained hypoxia which decreased peripheral chemosensitivity. Interestingly, the peripheral chemosensitivity to brief hypoxic stimulation following the relief from sustained hypoxia was initially blunted, but gradually increased at a rate of 1.9% per minute and was completely recovered by 36 min. Together with the results reported by Bascom et al. (1990), the findings from the present study demonstrate that the changes occurring at the level of the carotid bodies due to sustained hypoxia require more time to revert back, or recover, to initial conditions.
While changing the peripheral chemoreflex control of 
will alter the convective transport of O2 at the lungs, the increase in CBF during both sustained and acute hypoxia in the present study was sufficient to offset the reduction in O2. The increase in CBF ensured that the brain received an adequate O2 supply and that the effects of central hypoxia were avoided.
Although the response to hypoxia has been described in older adults (Ahmed et al. 1991; Smith et al. 2001), to date these are the only data on the ventilatory recovery from HVD in older subjects. In conjunction with the findings of Smith et al. (2001), the characteristics of the hypoxic ventilatory response, its decline and recovery are unaffected by age in individuals who are healthy and active. While CBF was not measured in the older group in the present study, it is expected that CBF would respond in a similar fashion to their younger counterparts.
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values collected during hypoxic pulses (*) were used. For the series method, all 
values from all 4 trials were used. Numbers indicate time of hypoxic pulse following the relief from sustained hypoxia (post-HVD).
(top) and cerebral blood velocity in the MCA (bottom) in 1 representative subject following protocol A 
, the magnitude of CBV responses did not change during the course of sustained hypoxia or during the hypoxic pulses.
responses were significantly different from 100% (initial 
) except for the hypoxic pulses 35 and 41 min post-HVD, indicating that resensitization of the peripheral chemoreceptors was complete by 35 min.
) 
, blood gases and CBV in group 1 (young) following protocol A
between methods or age, indicating that peripheral chemosensitivity recovers at the same rate regardless of the method used or the age of the subject. Ventilation was significantly different from 100% (where 100% represents the initial ventilatory response to sustained hypoxia) for all data points, indicating that resensitization of the peripheral chemoreceptors was not complete.
and blood gasses between groups 2 (young) and 3 (older) following protocol B