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O2 max after altitude
acclimatization still reduced despite normalization of arterial
O2 content?
1 Department of Physical Education, University of Las Palmas de Gran Canaria, 35017 Las Palmas de Gran Canaria, Spain; 2 The Copenhagen Muscle Research Centre, Rigshospitalet, 2200 Copenhagen N, Denmark; 3 Department of Exercise Science, Concordia University, Montreal, Quebec, Canada H4B 1R6; and 4 Department of Medicine, Section of Physiology, University of California San Diego, La Jolla, California 92093
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Acute hypoxia (AH) reduces maximal
O2 consumption (
O2 max),
but after acclimatization, and despite increases in both hemoglobin
concentration and arterial O2 saturation that can normalize arterial O2 concentration ([O2]),
O2 max remains low. To determine why,
seven lowlanders were studied at O2 max (cycle ergometry) at sea level (SL), after 9-10 wk at 5,260 m [chronic hypoxia (CH)], and 6 mo later at SL in AH
(FIO2 = 0.105) equivalent to
5,260 m. Pulmonary and leg indexes of O2 transport were
measured in each condition. Both cardiac output and leg blood flow were
reduced by ~15% in both AH and CH (P < 0.05). At
maximal exercise, arterial [O2] in AH was 31% lower than
at SL (P < 0.05), whereas in CH it was the same as at
SL due to both polycythemia and hyperventilation. O2
extraction by the legs, however, remained at SL values in both AH and
CH. Although at both SL and in AH, 76% of the cardiac output perfused
the legs, in CH the legs received only 67%. Pulmonary
O2 max (4.1 ± 0.3 l/min at SL)
fell to 2.2 ± 0.1 l/min in AH (P < 0.05) and was
only 2.4 ± 0.2 l/min in CH (P < 0.05). These
data suggest that the failure to recover O2 max after acclimatization despite
normalization of arterial [O2] is explained by two
circulatory effects of altitude: 1) failure of cardiac
output to normalize and 2) preferential redistribution of
cardiac output to nonexercising tissues. Oxygen transport from blood to
muscle mitochondria, on the other hand, appears unaffected by CH.
cardiac output; fatigue; performance; exercise; cardiovascular physiology; maximal oxygen consumption
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE REASON WHY maximal
O2 consumption (O2 max) and
maximal exercise capacity remain substantially reduced after
high-altitude acclimatization, despite arterial O2 content
(CaO2) increasing to match or even surpass the
values observed at sea level (SL), is unknown (5, 8, 40,
47). In moderate acute hypoxia (AH),
O2 max is reduced in the same
proportion as CaO2 is lowered. Despite the
reduction in maximal cardiac output in chronic hypoxia (CH) (35,
40), systemic O2 delivery
(CaO2 × cardiac output) increases to
values close to those observed at SL owing to the greater blood
hemoglobin concentration ([Hb]) and arterial O2
saturation (SaO2) after acclimatization
(8, 47). However, O2 max
either remains at the same level as in AH or increases only slightly
with acclimatization (5, 8, 40, 47). Thus, there is a
dissociation between maximal systemic O2 delivery and
O2 max during exercise in hypoxia after
altitude acclimatization, the mechanisms of which remain unknown.
A reduction in muscular oxidative capacity with altitude
acclimatization seems unlikely because hyperoxia at altitude
immediately restores SL O2 max
(5, 8, 40, 47). It has been suggested that altitude
acclimatization could impair O2 diffusion from the
capillaries to the muscular mitochondria (5, 8, 40, 47),
despite that the off-loading and diffusion of O2 from
hemoglobin to the muscular mitochondria are facilitated by two
consequences of acclimatization, a rightward shift of the O2-hemoglobin dissociation curve (12, 41) and
an increase in capillary density (28).
An alternative explanation is the possibility of an alteration in the distribution of blood flow between tissues competing for O2 during intense exercise in CH reducing blood flow to the muscles. At altitudes up to 4,000 m, peak leg blood flow (LBF) has been reported to equal that observed in normoxia (5, 42), suggesting this is not a tenable explanation. However, to date, no studies have examined how the available cardiac output is partitioned to contracting muscle and other tissues during maximal exercise after acclimatization to higher altitudes.
The aim of this investigation was to determine why
O2 max is not improved (or only
marginally increased) after acclimatization to high altitude by
studying the impact that altitude acclimatization has on the different
steps composing the O2 transport system. The two main
possibilities are 1) reduction in the maximal delivery of
O2 to the exercising muscles due to changes in peak
muscular blood flow and/or the distribution of cardiac output and
2) alterations in the diffusion or utilization of
O2 by the active muscles. To explore these mechanisms, the
cardiovascular response to exercise was studied in healthy humans after
9-10 wk of permanence at 5,260 m, in Chacaltaya (Bolivia), in
conditions of hypoxia and at least 6 mo later in AH equivalent to 5,260 m.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
Seven healthy Danish lowlanders (3 females and 4 males) volunteered to participate in these studies. Their mean (±SE) age, height, and weight were 24.0 ± 0.6 yr, 176 ± 3 cm, and 74 ± 4 kg, respectively. The health status of each subject was assessed by a complete medical history and physical examination. All had a normal resting ECG, as well as normal liver, kidney, and thyroid function and normal fasting plasma glucose and electrolyte concentrations. Iron status was also normal for males and females as reflected by blood [Hb] (145 ± 6 and 122 ± 2 g/l) and transferrin (31.3 ± 0.3 and 32.7 ± 1.9 µmol/l). However, plasma concentrations of ferritin were normal for males and slightly reduced in two of the females (74 ± 23 and 24 ± 11 µg/l). The subjects were informed about the procedures and risks of the study before giving written informed consent to participate as approved by the Copenhagen-Fredriksberg Ethical Committee. The "Guiding Principles for Research Involving Animals and Human Beings" of the American Physiological Society were strictly followed (2).Experimental Design
As part of preliminary examinations ~2 mo before altitude exposure, subjects performed an incremental exercise test to exhaustion on a cycle ergometer (120-W initial work rate increased by 40 W every 1 min).O2 max averaged 61 ± 0.5 ml · kg
1 · min1 for the
males and 50 ± 3 ml · kg1 · min1 for the females.
CH tests were conducted at altitude after 9- to 10-wk residence at 5,260 m on Mount Chacaltaya, Bolivia. During this time, two short expeditions (2-4 days) were carried out to peaks at 6,080 (Monte Potosí) and 6,500 m (Monte Illimani), respectively. The latter expedition took place 3-5 days before the start of the experiments. AH tests at SL were carried out at least 6 mo after the subjects returned to Denmark, after just a few minutes exposure to hypoxic gas.
Subjects performed upright, submaximal, and maximal cycling exercise at altitude and at SL with two different fractions of inspired O2 (FIO2). During the experiments at altitude, the subjects inspired room air (408 mmHg, PIO2 = 76 mmHg) and air from a tank containing 55% O2 in nitrogen (PIO2 = 200 mmHg). Experiments at SL were carried out at a barometric pressure of 750-760 mmHg with two different levels of FIO2, 0.210 (room air) and 0.105 (from a premixed tank of O2 in nitrogen). The latter resulted in a PIO2 similar to that observed at altitude (i.e., 75 mmHg).
Experimental Preparation
An 18-gauge catheter (Hydrocath, Ohmeda, Swindon, UK) was inserted percutaneously while the subjects were under local anesthesia (2% lidocaine) into either the right or left femoral vein, 2 cm below the inguinal ligament and advanced 7 cm distally for venous sampling and injection of cold saline. A thin polyethylene-coated thermistor (model 94-030-2.5F T.D. Probe, Edwards Edslab, Baxter, Irvine, CA) was then inserted 3 cm below the inguinal ligament and advanced proximally 10 cm into the same femoral vein. A second 18-gauge catheter was then placed into the femoral artery 2 cm below the inguinal ligament and advanced 14 cm proximally for arterial sampling and blood pressure measurement. The catheters were connected to a three-way stopcock and, along with the thermistor, sutured to the skin to minimize the risk of movement during exercise. An additional catheter was placed in a vein in the left forearm for the injection of the Cardio-green dye. After catheter placement, the subjects rested in the supine position for 30 min before the exercise test.Exercise Protocol
Two different kinds of exercise tests were performed: submaximal constant intensity and incremental exercise on the cycle ergometer (Monark 824 E, Vadberg, Sweden) until exhaustion. Thirty minutes after catheterization, subjects sat on the cycle ergometer and breathed through a two-way valve inspiring room air (CH) or 10.5% O2 (AH) for 5 min before rest measurements were made (Fig. 1). Subjects then cycled at the highest intensity they could tolerate for 10 min (known from preliminary tests) when exercising in AH (102-141 W, at 80 revolutions/min). Measurements were made at 6 and 10 min. Subsequently, after resting for ~10 min in CH and 20-30 min in AH, the maximal exercise test was started at an initial intensity identical to that used in the submaximal test. This was maintained for 2 min. Exercise intensity was then increased rapidly to 90% of previously determined peak levels (Wmax). After 2 min, measurements were made and the load was increased as tolerated to maximal levels by ~20-40 W every min until reaching the maximal exercise intensity (Wmax). Load increments were adjusted such that the exercise duration of the incremental exercise tests was ~6-7 min in all conditions. Just at the end of the exercise with hypoxia, subjects were vigorously encouraged to keep pedaling while they were switched to breathe hyperoxic air (FIO2 = 0.55), giving a PIO2 of ~200 mmHg in CH, or room air at SL in the AH study. After 2 min at this PIO2, a further set of measurements was made, and finally the workload was increased again in steps of 20-40 W every min, and close to exhaustion measurements were repeated. In this way, the same protocols and O2 exposure profiles were used in both AH and CH.
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Measurements
Respiratory variables.
Pulmonary O2, CO2 production
(CO2), and expired minute ventilation
(E) were measured continuously with an on-line
system (Medical Graphics CPX, Saint Paul, Minneapolis, MN) and averaged every 15 s. Gases with known O2 and CO2
concentrations (micro-Scholander) were used for gas analyzer
calibration before every test. During submaximal exercise, the
O2 values obtained during the last 4 min
were averaged. During the incremental exercise, the highest O2 value recorded during any single 15-s
interval was taken as the O2 max. The
system operated only when ambient air was breathed, and thus no data
were obtained in hyperoxia (i.e., 55% in CH).
Blood flow.
Femoral venous blood flow (i.e., LBF) was measured in the femoral vein
by constant-infusion thermodilution as described in detail in our
companion article (3). Briefly, iced saline was infused
through the femoral vein catheter at flow rates sufficient to decrease
blood temperature at the thermistor by 0.5-1°C. Infusate and
blood temperature were measured continuously during saline infusion
(Harvard pump, Harvard Apparatus, Millis, MA) via thermistors connected
to the data-acquisition system (MacLab 16/s ADInstruments, Sydney,
Australia). Blood flow was calculated on thermal balance principles, as detailed by Andersen and Saltin (3).
Resting blood flows were measured in triplicate and averaged. During
submaximal exercise, blood flow was measured twice, at 6 and 9 min. The
reported value for each exercise load represents the average of the
four measurements. At peak effort, the measurements were made within 1 min of exhaustion. When possible, duplicate measurements of LBF and
femoral arteriovenous O2 differences were made during the
brief period of peak exercise. Heart rate (HR), arterial blood pressure, pulmonary O2,
CO2, and E were
measured at the same time as LBF and cardiac output.
Blood pressure and HR. Intra-arterial blood pressure was measured with a disposable transducer (T100209A, Baxter, Unterschleissheim, Germany) placed at the level of the inguinal ligament. A three-lead ECG was used to measure HR and displayed on a monitor (Dialogue 2000, Danica, Copenhagen, Denmark) during the experimental and recovery phases. The blood pressure and ECG signals were recorded with the data-acquisition system. Systolic and diastolic arterial pressures were computed from the recorded pressure wave, as the maximum and minimum values registered in each cardiac cycle. Mean arterial blood pressure (MAP) was calculated as the integral of the pressure-wave curve over time. Average values corresponding to the blood flow measurement period were recorded for further calculations.
Cardiac output. Cardiac output was measured by indocyanine green (Akorn) dye-dilution (14), as described in detail in our companion article.
Blood Analysis
Blood [Hb] and O2 saturation (SO2) were measured with a cooximeter (OSM 3 Hemoximeter, Radiometer, Copenhagen, Denmark). PO2, PCO2, and pH were determined with a blood gas analyzer (ABL 5, Radiometer). From these values, plasma HCO
Calculations
Arteriovenous O2 concentration ([O2]) difference (a-vO2diff) was calculated from the difference in femoral arterial and femoral venous [O2]. This difference was then divided by arterial concentration to give O2 extraction. Oxygen delivery was computed as the product of blood flow and CaO2. LegO2 was calculated as the product of LBF
and a-vO2diff. Non-leg O2
was computed as the difference between pulmonary
O2 and 2 × leg
O2. Leg plasma flow (LPF) was calculated
as the product of LBF and (1 
hematocrit). Net leg lactate and
potassium release were calculated as the product of LBF and LPF, the
venous-arterial difference of blood lactate, and plasma K+
concentrations, respectively. The standard P50, defined as
the values of PO2 that cause hemoglobin to be
saturated by 50% when the O2-Hb equilibration curve is
determined at 37°, pH = 7.40, PCO2 = 40 mmHg, was calculated from the whole set of arterial and venous
gases obtained in each experiment for the acclimatized and
unacclimatized state. Blood gas variables were corrected to and
expressed at body temperature.
Statistical Analysis
Differences in the measured variables among conditions and exercise levels were analyzed with two-way ANOVA for repeated measures, with altitude acclimatization and exercise intensity as within-subjects factors. When F was significant in the ANOVA, planned pair-wise-specific comparisons were carried out using Student's paired t-test adjusted for multiple comparisons with the Bonferroni procedure. Simple linear regression analysis was performed to determine linear relations between variables. Significance was accepted at P < 0.05. The influence of altitude acclimatization on the slope of the relationship between blood flow and cardiac output was assessed using analysis of covariance, with blood [Hb] as covariate. Data are reported as means ± SE.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Blood Gases and Acid-Base Balance
Exposure to altitude and AH resulted in similar significant decreases in PaO2 and SaO2 at rest (Table 1). During AH, this led to a significant decrease in CaO2. Nine- to 10-wk exposure to high altitude, however, increased blood [Hb] by 36% compared with that at SL (182 ± 0.4 vs. 135 ± 5 g/l). As a result, despite the decreases in PaO2 and SaO2, CaO2 at rest after acclimatization to altitude was 19% higher than it was during normoxia at SL (218 ± 6 vs. 180 ± 2 ml/l). Compared with AH, acclimatization resulted in lower resting values of PaCO2, PvCO2, pHa, arterial and venous HCO
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As expected, PaO2 and
SaO2 during exercise were significantly reduced
in both CH and AH (Table 1). However, the decreases during AH were
greater than those in CH. Consequently, CaO2
decreased with exercise intensity but more steeply in AH than CH.
Femoral venous blood gases (SfvO2,
PfvO2, and CfvO2)
during exercise were markedly reduced, an effect that was accentuated
in AH compared with CH (Table 1). Although exercise resulted in a fall
in arterial pH, the decrease during AH was blunted slightly compared
with CH. CH and AH each resulted in parallel reductions in
arterial plasma HCO
P50 values (expressed at 37°, for pH = 7.40 and PCO2 = 40 mmHg) were increased from 24.5 ± 0.3 at SL (AH) to 30.5 ± 0.6 after altitude acclimatization.
Pulmonary Gas Exchange, Cardiac Output, and Systemic O2 Delivery
Although pulmonary ventilation remained unchanged during submaximal exercise (Fig. 2A), the alveolar PO2 was increased by 9% (Fig. 2B) while the A-aDO2 was reduced by 39% (Fig. 2C) with acclimatization. Consequently, submaximal exercise arterial oxygenation was substantially improved as reflected by enhancement of PaO2 (43%) and SaO2 (19%) with acclimatization (Table 1).
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Submaximal exercise pulmonary O2 was
similar in AH and CH (Fig. 2D), despite a 15% lower cardiac
output after acclimatization, which, however, allowed a higher
O2 delivery than in AH due to the acclimatization-induced
elevation in blood [Hb].
Maximal exercise ventilation increased by 29% with acclimatization, attaining the same value as at SL (Fig. 2A). The corresponding alveolar PO2 was higher by 9% (Fig. 2B) and the A-aDO2 lower by 26% (Fig. 2C), leading to improved oxygenation at maximal exercise after acclimatization, as reflected by the increase in PaO2 (34%) and SaO2 (7%, P = 0.33) (Table 1).
Maximal power output was not significantly increased, but maximal
pulmonary O2 was 13% higher after
acclimatization than it was in AH (Fig. 2A)
(P < 0.05). However,
O2 max after acclimatization was still
26% lower than at SL (Fig. 2D). The subjects with the
greatest normoxic O2 max tended to improve their hypoxic O2 max more with
acclimatization (r = 0.66, P = 0.10).
Maximal cardiac output values were similarly reduced (i.e., by ~15%,
P < 0.05) in CH and AH compared with normoxia at SL or hyperoxia at altitude. The effect of CH on cardiac output, however, was
rapidly and completely reversed with hyperoxia at altitude (Fig.
3A). HR during submaximal and
maximal exercise was 15-20% lower after acclimatization (Fig.
3C). This difference was halved with hyperoxic breathing at
altitude. The maximal stroke volume was higher after acclimatization
(Fig. 3E) (P < 0.01).
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As shown in Fig. 3B, altitude acclimatization resulted in a marked increase (37-54%) in systemic O2 delivery compared with AH. Similarly, systemic a-vO2diff was higher during CH than AH (Fig. 3D). Consequently, systemic O2 extraction during exercise ranged between 63 and 67% after altitude acclimatization, while it attained values close to 87% during AH (Fig. 3F) (P < 0.001). A close linear relationship was observed between exercise intensity and cardiac output (r = 0.98, P < 0.001).
LBF, Leg O2, and Muscle-Diffusing
Capacity
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Despite this reduction in maximal LBF with hypoxia, maximal oxygen delivery to the legs during hypoxia was higher by 40% in CH than AH (Fig. 4C). However, it was still 24% lower than that observed in normoxia at SL. This increase in leg O2 delivery was reflected in significant differences in femoral a-vO2diff between CH and AH (Fig. 4B). The fraction of O2 extracted by the legs was similar in CH and AH, while it was reduced with the hyperoxic gas at altitude (Fig. 4D).
Leg O2 during submaximal and maximal
exercise was increased by 42 and 39% after altitude acclimatization
(P < 0.001). Peak leg
O2 after altitude acclimatization
remained, however, 21% below the value attained in normoxia at SL
(Fig. 4E) (P < 0.05). Muscle O2
conductance (represented by the slope of the relationship between peak
leg O2 and capillary
PO2) was similar before and after altitude
acclimatization (Fig. 4F), under all conditions (except
hyperoxia at altitude, where O2 max
failed to increase in proportion to capillary
PO2).
In addition, leg O2 was closely related
to leg O2 delivery (r = 1, P < 0.001) as was LBF to cardiac output
(r = 0.86, P < 0.01). When the
conditions with different blood [Hb] were analyzed separately, the
coupling between LBF and cardiac output was even more evident, as shown
in Fig. 5. Moreover, the slope of the
relationship between LBF and cardiac output was less accentuated after
altitude acclimatization than in AH (P < 0.05).
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Distribution of Cardiac Output
During submaximal exercise, similar proportions of cardiac output were directed to tissues other than the exercising legs in CH and AH (4.1 ± 0.5 and 5.3 ± 0.8 l/min, respectively). At maximal exercise, however, blood flow to regions other than the legs was enhanced in CH compared with AH (6.6 ± 0.8 vs. 4.8 ± 0.9 l/min, respectively, P = 0.05). Although at both SL and in AH, 76% of the cardiac output perfused the legs, in CH the legs received only 67%. With hyperoxic breathing at altitude, noncontracting tissue blood flow during maximal exercise was additionally increased to 8.8 ± 1.2 l/min, this value being significantly higher than that observed at maximal exercise in normoxia (4.7 ± 0.6 l/min; P < 0.05). Furthermore, the amount of blood flow diverted to regions other than the legs during maximal exercise also appeared to be related to CaO2 as indicated by the close linear relationship between the lumped vascular conductance across these regions and CaO2 (r = 0.81, P = 0.05).MAP, Systemic Vascular Conductance, and Leg Vascular Conductance
MAP during exercise after altitude acclimatization was 11-13 mmHg higher than in AH (Fig. 6A). This increase in MAP was brought about by mainly an increase in diastolic blood pressure. Compared with AH, systemic vascular conductance was reduced after acclimatization but only during submaximal exercise (Fig. 6B). Likewise, leg vascular conductance tended to be reduced after acclimatization, reaching a maximal value that was lower than that attained during maximal exercise in normoxia (Fig. 6C).
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Plasma Catecholamines
Arterial and venous plasma norepinephrine concentrations at rest were elevated following altitude acclimatization (2.3-2.4 nmol/l) compared with those at SL after 3-5 min of AH (0.7 ± 0.1 nmol/l). During submaximal exercise, plasma norepinephrine concentrations increased similarly in CH and AH. However, when the conditions with a similar CaO2 were compared (i.e., maximal exercise intensity in CH and the same intensity with normoxia), CH elicited a higher noradrenaline response (Fig. 7). Even at maximal exercise with hyperoxia after altitude acclimatization, plasma norepinephrine was slightly higher than when breathing atmospheric air (P = 0.06). By contrast, arterial and venous plasma concentrations of epinephrine tended to be higher after altitude acclimatization, but differences were not statistically significant. Interestingly, arterial plasma concentrations of epinephrine correlated with cardiac output (r = 0.76, P < 0.05).
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Blood Lactate and Potassium
Arterial and venous blood lactate concentrations were significantly higher in both CH and AH than they were in normoxia (Table 1), leading to a higher lactate release during exercise in CH. By contrast, lactate release was significantly reduced by hyperoxic breathing. In addition, arterial blood lactate concentrations correlated with cardiac output (r = 0.74, P < 0.05), PaO2 (r =0.73, P < 0.05) and the
arterial plasma concentrations of epinephrine (r = 0.88, P < 0.01) and norepinephrine (r = 0.85, P < 0.01). Net lactate release, on the other
hand, correlated with the plasma arterial concentration of epinephrine
(r = 0.75, P < 0.05).
Femoral venous plasma [K+] was greater than arterial concentrations in all conditions, indicating a net release of K+ that was more accentuated during submaximal exercise after altitude acclimatization than in AH (P < 0.05). Arterial plasma [K+] was closely related to LBF (r = 0.73, P < 0.05), cardiac output (r = 0.93, P < 0.01), and arterial blood [La] (r = 0.85, P < 0.01). Leg potassium release, on the other hand, correlated with MAP (r = 0.72, P < 0.05), LBF (r = 0.74, P < 0.05), and cardiac output (r = 0.82, P < 0.05).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study shows that O2 max at
altitude is not improved with acclimatization as much as would be
expected (given the increase of the maximal capacity for O2
transport to near maximal SL values) because most of the extra
O2 available is distributed to other tissues than the
exercising muscles. The effects of altitude acclimatization on the main
steps of the oxygen transport system are discussed below.
Cardiac Output and Systemic O2 Delivery
Since the pioneer publication by Pugh et al. (35), investigators have consistently found a decrease in maximal cardiac output with CH starting at altitudes higher than 3,100 m and for exposure durations up to 5 wk, a response that is more accentuated as the altitude of the residence is increased (20, 24, 40, 47). Our study expands on these observations and demonstrates that this decrease is still present after 9-10 wk of acclimatization to high altitude. Interestingly, maximal cardiac output was reduced to the same extent in AH, which contrasts with previous studies reporting similar maximal cardiac outputs in normoxia and AH (23, 24, 44, 49). This discrepancy is likely caused by the severity of the AH exposure elicited in the present study that caused the PaO2 to drop to the limit that a human can tolerate acutely (30-34 mmHg). A similar PaO2 drop (to 29-31 mmHg) was reported in subjects progressively decompressed to the barometric pressure equivalent to the summit of Mt. Everest during Operation Everest II experiments (36, 47). In AH as well as in CH, SL maximal cardiac outputs were restored just by increasing PaO2 and SaO2 to SL or mildly hyperoxic values. This implies that the mechanism causing the reduction in maximal cardiac output is directly related to the PaO2 and relatively independent of CaO2.Severe hypoxemia may account for the acute reduction in cardiac output acting directly on the heart (1) or indirectly by attenuating the output drive to the heart from the cardiovascular nuclei in the central nervous system (46). There is no evidence from this or other studies suggesting that myocardial O2 supply deficit could have accounted for the reduction in maximal cardiac output, inasmuch as when the subjects were switched to breathe under normoxic or hyperoxic conditions, cardiac output did not increase until exercise intensity was augmented. In agreement, even with more severe hypoxemia, no sign of impairment in myocardial function has been reported (30, 36). The possibility of insufficient myocardial O2 delivery in CH is even less plausible. Although the O2 inspiratory pressures were identical, the degree of hypoxemia was considerably higher in AH than in CH likely due to the improvement of pulmonary gas exchange and ventilation with acclimatization to high altitude (48). In addition, the marked enhancement in blood [Hb] and the improvement in SaO2 with acclimatization allowed for a recovery of CaO2 to values similar to those observed during maximal exercise in normoxia. With comparable CaO2, myocardial O2 delivery was probably also similar during exercise in CH and normoxia.
It has been proposed that the reduction in maximal cardiac output after
altitude acclimatization may be caused by the reduction in maximal HR
observed in CH (17, 26). A lower maximal HR does not
appear to be the main mechanism responsible for the reduction in
maximal cardiac output since with hyperoxia, HR was increased without
significant changes in cardiac output due to the reduction of stroke
volume. In addition, we recently showed that the increase of maximal HR
to match at altitude the values attained at SL does not enhance maximal
cardiac output or O2 max
(6).
An alternative explanation is that severe hypoxemia may have altered the capacity to fully activate motor units and thus caused a decrease in maximal exercise intensity. A reduction in maximal exercise intensity would attenuate the "muscle pump" action and likely reduce venous return and, therefore, cardiac output. In favor of this hypothesis, it should be considered that cardiac output was closely related to exercise intensity in all conditions. Yet it could also be the case that centrally mediated blunting of cardiac output by low PO2 may attenuate LBF, which would in turn limit muscle work capacity.
Although maximal cardiac output was similar in AH and CH, maximal
systemic O2 delivery was considerably enhanced by
acclimatization, being 54% higher after acclimatization than in AH,
reaching a value that was just 11% below that attained during maximal
exercise in normoxia. Nonetheless, after acclimatization,
O2 max was only 13% higher than in AH
and remained 26% lower than in normoxia. If we compare, however, the
improvement in O2 max observed in the
present study with, for example, the 18% increase elicited by 8 wk of
training at SL in college students (39), our
interpretation would have been that acclimatization resulted in a great
improvement of O2 max, especially
taking into account that the subjects remained physically active but
did not train systematically with the aim of improving their
O2 max. However, the fact that we would
like to highlight is that this improvement in
O2 max is rather small compared with
the remarkable improvement of systemic O2 delivery, i.e.,
potentially O2 max could have increased
much more than it actually did. This finding is in accordance with
previous studies showing marginal improvements or lack of change in
O2 max with acclimatization, despite
substantial improvements in maximal O2 delivery (5,
16, 40, 47).
The results of this study demonstrate that the main reason why
O2 max is not improved as would be
expected given the large increase in systemic O2 delivery
with altitude acclimatization is that only a portion of the enhanced
O2 transport capacity is made available to the locomotor
muscles. In AH, a major proportion of the blood flow is deviated to the
working legs leaving only 4.8 l/min to supply the rest of the vascular
beds. This value is slightly lower than the 5.1 reported by Kjaer et
al. (30) during semirecumbent cycling exercise in moderate
hypoxia (FIO2 = 0.115). It
should be mentioned, however, that the intensity of the exercise used
by Kjaer et al. (30) was high but not maximal. In this
study, the amount of blood flow directed to noncontracting tissues in
CH was 37% higher than in AH at the expense of reducing the amount of
flow directed to the exercising muscles. Actually, combining all the
conditions included in this study and using linear regression analysis
with blood [Hb] as covariate, it became very clear that a greater
proportion of the cardiac output is directed to noncontracting tissues
the higher the CaO2, especially at maximal
exercise. As a consequence, the extra O2-carrying capacity of blood gained with altitude acclimatization could only be marginally exploited by the exercising muscles, which limited the improvement of
O2 max to one-third of what would have
been possible if the regional distribution of blood flow during
exercise in hypoxia was kept similar after altitude acclimatization to
that observed in AH. This pattern allows modest improvements in maximal work capacity at altitude while ensuring improvements in the
O2 supply to noncontracting tissues.
Regulation of LBF
In agreement with our previous work, the bulk of our data indicates that at the same absolute exercise intensity, the elevation of CaO2 is counterbalanced by a reduction in LBF (31, 32, 38) such that O2 delivery to the working muscles is maintained. Nonetheless, our results suggest also that in acute severe hypoxia, the elevation of LBF is insufficient to completely account for the diminution in CaO2 and, hence, a situation is created in which O2 delivery does not match O2 demand, requiring a complementary activation of anaerobic energy pathways. This is supported by the fact that during submaximal exercise, legO2
was lower in AH than in CH (52).
In AH, the amount of blood flow directed to the vascular beds apart
from the contracting skeletal muscles was minimal, yet a further degree
of redistribution of blood flow to the legs would have likely
compromised the supply of O2 to critical organs. Therefore, if the degree of redistribution of blood flow to the exercising muscles
was maximal, or nearly maximal, the only mechanism left to increase LBF
would have been an elevation of cardiac output. Compared with AH, leg
vascular conductance was lower after acclimatization, but the
conductance across noncontracting tissues was higher. Had this
adaptation in the regulation of vascular conductances not occurred, it
is clear that O2 max in CH would have been ~11% higher than observed. Thus, the fall in
O2 max with acclimatization would have
been 15%, almost matching the 11% reduction in systemic
O2 delivery observed after acclimatization. Thus, an
important adaptation to high altitude is that blood flow priority is
given to the low O2 demand of the noncontracting tissues over the high metabolic demand of the exercising skeletal muscles. Given the increased maximal exercise E after
acclimatization, a greater blood flow supply to the respiratory muscles
after acclimatization is also plausible (22).
A noteworthy finding from this study is that during submaximal exercise, net K+ release was higher after altitude acclimatization than in AH. In contrast, exercise-net K+ release was similar in AH and normoxia, as previously reported (31), suggesting that this effect is a consequence of the acclimatization process. Net K+ release depends on the balance between K+ uptake and K+ release. Muscle K+ uptake depends mainly on the activity of the Na+-K+ pump, which increases with exercise intensity (9). Recent studies showed that CH is associated with a downregulation of the Na+-K+-ATPase pumps (18, 19) and increased plasma concentration of an endogenous inhibitor of Na+-K+-ATPase pumps (13) similar to ouabain (27). Both mechanisms could have led to reduced muscular K+ uptake after acclimatization. The potassium released from the active muscles may act on the central chemoreceptors increasing ventilation and the sympathetic drive to the heart and muscles (33). In agreement, compared with AH, a more accentuated norepinephrine response to exercise has been observed in the present study and others (34) after altitude acclimatization.
Effect of Acclimatization on Pulmonary Gas Exchange
Although resting PaO2 was similar in AH and CH, pulmonary gas exchange was impaired with exercise in both conditions but to a greater extent before than after acclimatization. As reported in our companion paper, PaO2 fell from 47 mmHg at rest to 34 mmHg at maximal exercise in AH, whereas after acclimatization, PaO2 decreased from 49 to 45 mmHg, i.e., the fall in PaO2 was only one-third of that observed before acclimatization. Two main mechanisms accounted for this enhancement of PaO2 after acclimatization: an increase in PaO2 and the improvement of pulmonary gas exchange, as reflected by the reduction in the A-aDO2 after acclimatization. The enhancement of PaO2 at maximal exercise was by 5 mmHg and is probably a direct consequence of the greater maximal ventilation after acclimatization.The 6-mmHg reduction of A-aDO2 after acclimatization could
be due to reduced ventilation-perfusion inequality and pulmonary shunt
and/or increased lung-diffusing capacity (49, 50).
Previous studies unequivocally showed that ventilation-perfusion
mismatch accounts for a small part of the A-aDO2 during
submaximal and near-maximal exercise in AH and CH (49,
50), while shunt has been excluded as a factor contributing to
the A-aDO2 during exercise in hypoxia (49) in
the absence of pulmonary edema. Therefore, an improvement in
lung-diffusing capacity appears likely to be the main mechanism
responsible for the decrease of A-aDO2 with acclimatization. The total lung-diffusing capacity is composed of two
main components: the membrane-diffusing capacity
(DMO2) and the blood (or erythrocyte)-diffusing
capacity (DeO2). The membrane-diffusing
capacity is principally determined by structural factors that likely do
not change with acclimatization in lowlanders. Thus, any putative
improvement of diffusive conductance should be explainable by an
enhancement of DeO2. The blood-diffusing capacity is primarily determined by the capillary blood volume, [Hb],
and hemoglobin affinity for O2 (P50)
(15). The 36% higher blood [Hb] would have also
improved lung-diffusing capacity by reducing the spacing of red blood
cells within the capillaries (25). In contrast, the
increase of P50 with acclimatization reduces effective
O2 solubility in blood for a given
PaO2 and, thus, could impair the erythrocytic
component of total lung-diffusing capacity. In fact, the improvement in
SaO2 after acclimatization would have been 10%
higher if the P50 had remained unchanged with acclimatization, as illustrated in Fig.
8. Because arterial pH and blood
temperature were rather similar at maximal exercise in AH and CH, the
left shift effect elicited by the respiratory alkalosis was
counterbalanced after acclimatization by the increase in
P50, bringing the oxyhemoglobin dissociation curve to the
same position as that observed in normoxia before acclimatization (see Fig. 7 of our companion paper).
|
Another factor that could have also influenced gas exchange after acclimatization is the time available for diffusion equilibration between the alveoli and the pulmonary capillaries, which depend on the mean transit time of blood across the alveolar capillary bed (4). Although the fact that maximal cardiac output was similar in both conditions argues against such a mechanism, we cannot rule it out completely as acclimatization could have facilitated greater recruitment of alveolar capillaries or increased the pulmonary blood volume during maximal exercise. The higher ventilation attained after acclimatization could have also contributed to attenuate the magnitude of the A-aDO2 since, as shown by West (51), venous admixture and A-aDO2 will fall as a lung with a fixed degree of ventilation-perfusion mismatch is hyperventilated.
Even at SL, intense exercise is associated with some fluid accumulation in the pulmonary interstitial space (7), which is accentuated in AH (10). Thus, part of the A-aDO2 reduction with acclimatization would be explainable if acclimatization results in a lower degree of pulmonary interstitial edema in response to maximal exercise, in severe hypoxia. Pulmonary interstitial edema may amplify A-aDO2 values both by decreasing DMO2 and by enhancing the ventilation-perfusion mismatch (10).
It should be noted that despite the improvement of arterial O2 during exercise after acclimatization, the effect on SaO2 was rather modest (5%) due to the increase in P50. Likely the increase of P50 facilitates O2 delivery in tissues that cannot use the Bohr effect as efficiently as do the working muscles to facilitate the off-load of O2 from the oxyhemoglobin (29). The higher P50 appears not to provide any special advantage as a mechanism to facilitate muscle O2 extraction during maximal exercise after altitude acclimatization as commented on below.
Muscular O2 Exchange and Diffusing Capacity
Our data also suggest no deterioration in blood-to-muscle O2 transfer, thus excluding this as a possible factor preventing restoration ofO2 max after
altitude acclimatization (Fig. 4F). Fractional
O2 extraction across the working legs was not different
between AH and CH, and therefore, virtually all of the increase in
O2 delivery was reflected in a higher leg
O2. Second, the O2
dissociation curve of the hemoglobin was shifted to the right in CH, as
shown by the higher P50 values observed after altitude
acclimatization. A right-shifted O2 dissociation curve per
se facilitates the O2 off-loading from the hemoglobin, especially at the active muscles as it allows Hb desaturation to occur
at higher levels of mean capillary PO2
(11, 37). However, in CH, greater hyperventilation and
lower PaCO2 would tend to move the dissociation curve
upward. With a higher mean capillary PO2, the
gradient driving the diffusion of O2 from the capillaries
to the muscular mitochondria is enhanced and, thus, the diffusion of
O2 would be facilitated (45). Calculations of
muscle diffusive conductance showed no difference between AH and CH.
Thus, this study does not provide any evidence of altered peripheral
limitation to the diffusion and/or utilization of O2 after
high-altitude acclimatization.
In summary, this study shows that both acute and chronic exposure to
severe hypoxia (5,260 m, equivalent to 10.5% inspired O2)
reduces maximal cardiac output by a rapidly reversible mechanism related to the level of hypoxia experienced. Despite this similarity in
maximal cardiac output, maximal systemic O2 delivery is
considerably greater after acclimatization due mainly to an increase in
blood [Hb] but also to an improvement of
SaO2. As a consequence, after high-altitude
acclimatization, systemic O2 delivery reached values that
were just 11% below and 54% higher than those observed in normoxia at
SL and in AH, respectively. Despite this,
O2 max was only increased by 13% due
to reduction in cardiac output and redistribution of blood flow to
noncontracting tissues. The reason why the cardiovascular system does
not substantially increase O2 delivery to the exercising
muscle after altitude acclimatization despite apparently sufficient
functional reserve remains unknown.
| |
ACKNOWLEDGEMENTS |
|---|
Special thanks are given to H. Wagner, C. Nielsen, K. Hansen, and B. Jessen for excellent technical assistance and G. Ordway for insightful comments. We also acknowledge the Academia de Ciencias de Bolivia and especially Dr. C. Aguirre for all the help and support to set our expeditionary lab at the heights of Mt. Chacaltaya. All the help and support provided by Dr. M. Araoz and Dr. H. Spielvogel are also greatly acknowledged.
| |
FOOTNOTES |
|---|
This study was supported by a grant from The Danish National Research Foundation (504-14). J. A. L. Calbet was on leave from the Department of Physical Education at the University of Las Palmas de Gran Canaria.
Address for reprint requests and other correspondence: J. A. L. Calbet, Departamento de Educación Física, Campus Universitario de Tafira, 35017 Las Palmas de Gran Canaria, Canary Islands, Spain (E-mail: lopezcalbet{at}terra.es).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published October 3, 2002;10.1152/ajpregu.00156.2002
Received 11 March 2002; accepted in final form 27 September 2002.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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C. Reboul, S. Tanguy, A. Gibault, M. Dauzat, and P. Obert Chronic hypoxia exposure depresses aortic endothelium-dependent vasorelaxation in both sedentary and trained rats: involvement of L-arginine J Appl Physiol, September 1, 2005; 99(3): 1029 - 1035. [Abstract] [Full Text] [PDF]
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C. H. E. Imray, S. D. Myers, K. T. S. Pattinson, A. R. Bradwell, C. W. Chan, S. Harris, P. Collins, A. D. Wright, and the Birmingham Medical Research Expeditionary Soci Effect of exercise on cerebral perfusion in humans at high altitude J Appl Physiol, August 1, 2005; 99(2): 699 - 706. [Abstract] [Full Text] [PDF]
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T. D. Noakes, J. A. L. Calbet, R. Boushel, H. Sondergaard, G. Radegran, P. D. Wagner, and B. Saltin Central regulation of skeletal muscle recruitment explains the reduced maximal cardiac output during exercise in hypoxia Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2004; 287(4): R996 - R1002. [Full Text] [PDF]
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J. A. L. Calbet, G. Radegran, R. Boushel, H. Sondergaard, B. Saltin, and P. D. Wagner Plasma volume expansion does not increase maximal cardiac output or VO2 max in lowlanders acclimatized to altitude Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1214 - H1224. [Abstract] [Full Text] [PDF]
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C. Marconi, M. Marzorati, B. Grassi, B. Basnyat, A. Colombini, B. Kayser, and P. Cerretelli Second generation Tibetan lowlanders acclimatize to high altitude more quickly than Caucasians J. Physiol., April 15, 2004; 556(2): 661 - 671. [Abstract] [Full Text] [PDF]
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B. A. Beidleman, S. R. Muza, C. S. Fulco, A. Cymerman, D. T. Ditzler, D. Stulz, J. E. Staab, S. R. Robinson, G. S. Skrinar, S. F. Lewis, et al. Intermittent altitude exposures improve muscular performance at 4,300 m J Appl Physiol, November 1, 2003; 95(5): 1824 - 1832. [Abstract] [Full Text] [PDF]
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J. A L Calbet Chronic hypoxia increases blood pressure and noradrenaline spillover in healthy humans J. Physiol., August 15, 2003; 551(1): 379 - 386. [Abstract] [Full Text] [PDF]
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) and after 9-10 wk at
5,260 m while breathing either ambient air (
) or
normoxia at sea level (
). * Significant differences
between acute and chronic hypoxia (P < 0.05);
¶significant differences between chronic hypoxia and normoxia, at
maximal exercise (P < 0.05); and §significant
differences between chronic hypoxia and normoxia at sea level at the
same exercise intensity (P < 0.05).
), heart rate (HR), stroke volume (SV), systemic
(Sys) O2 delivery, systemic O2 content
arteriovenous difference (Sys a-vO2 diff), and systemic
oxygen fractional extraction (Sys O2 extraction) during
submaximal and maximal exercise in acute hypoxia (
).
* Significant differences between acute and chronic hypoxia
(P < 0.05); ¶significant differences between chronic
hypoxia and normoxia, at maximal exercise (P < 0.05);
significant differences between chronic hypoxia and hyperoxia at
altitude, at the same absolute exercise intensity (P < 0.05); and §significant differences between chronic hypoxia and
normoxia at sea level at the same exercise intensity (P < 0.05).
