| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Journal of Physiology (2002), 545.2, pp. 715-728
© Copyright 2002 The Physiological Society
DOI: 10.1113/jphysiol.2002.029108
O2,max and cardiovascular function in lowlanders acclimatised to 5260 m |
ABSTRACT |
|---|
 TopAbstract IntroductionMethodsResultsDiscussionReferences |
|---|
The principal aim of this investigation was to determine the influence of blood haemoglobin concentration ([Hb]) on maximal exercise capacity and maximal O2 consumption (
(Resubmitted 23 July 2002; accepted after revision 20 September 2002; first published online 1 November 2002)
Corresponding author J. A. L. Calbet: Departamento de Educación Física, Campus Universitario de Tafira, 35017 Las Palmas de Gran Canaria, Canary Islands, Spain. Email: lopezcalbet{at}terra.es
|
INTRODUCTION |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
After a few weeks of hypoxic exposure, there is a well-known increase in haemoglobin concentration ([Hb]) in lowlanders coming to altitude. A high [Hb] is also characteristic of South American natives resident at altitude. This increase can be sufficient to offset the decrease in arterial O2 saturation (Sa,O2) caused by the reduced inspired PO2 and thus restore arterial O2 concentration to sea level values. Yet, when this occurs, O2,max is not returned to sea level values (Saltin et al. 1968; Bender et al. 1988; Sutton et al. 1988). This has led some to question whether the polycythaemia of altitude is of adaptive value or not. In fact, in Tibetan high altitude natives (Beall et al. 1998) and in some non-primate high altitude mammals such as the llama (Weiser et al. 1992), all of which have resided at altitude for a great many generations, [Hb] is only slightly higher than sea level values. Furthermore, Winslow postulated that acute reduction in [Hb] does not compromise maximal exercise capacity in South American high altitude natives after performing a single subject experiment (Winslow et al. 1985), but how this can occur in the face of large reductions in blood O2 carrying capacity has not been resolved. Richardson & Guyton (1959) long ago showed that as haematocrit was reduced, cardiac output was increased in compensation, and thus in the present circumstance it is possible that muscle blood flow might increase as [Hb] is reduced so as to preserve O2 delivery. Another possibility is that in natives of high altitude, maximal O2 is not limited by O2 availability, but rather by muscular oxidative capacity, such that maximal O2 is not dependent on systemic O2 transport (and thus not on [Hb]). The data of Favier et al. (1996) show in high altitude natives at 3600 m that increasing PI,O2 to sea level values produces only a small increase in maximal O2, perhaps because their subjects were not very fit or perhaps because living at high altitude had reduced their muscular oxidative capacity.
To distinguish among these possibilities, we determined the effects of acute, isovolaemic haemodilution on maximal exercise in a group of habitually active, acclimatised lowlanders who had spent 9 weeks at 5260 m prior to study. In so doing, we measured not only maximal work rates and O2, but also a range of cardiovascular and metabolic variables to provide insights into changes in O2 transport associated with haemodilution, and their possible mechanisms. Our general hypothesis was that despite the presence of O2 supply limitation of maximal exercise at 5260 m, isovolaemic haemodilution would not change O2,max, irrespective of changes in cardiovascular function. This hypothesis is based in part on theoretical calculations showing that if [Hb] were reduced at altitude, diminished convective circulatory O2 transport would be offset by improved diffusive transport of O2 at the lungs and muscles (Wagner, 1993).
|
METHODS |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Subjects
Eight healthy Danish lowlanders (three females and five males) volunteered to participate in these studies. Their mean (± S.E.M.) age, height and weight were 24.0 ± 0.6 years, 177 ± 3 cm and 76 ± 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. Their iron status also was normal for males and females as reflected by blood [Hb] (145 ± 4 and 122 ± 2 g l-1) and transferrin (31.3 ± 0.6 and 32.7 ± 1.9 µmol l-1). However, plasma concentrations of ferritin were normal for males and slightly reduced in two of the females (69 ± 19 and 24 ± 8 µg l-1). Overall, mean [Hb] was 136 ± 5 g l-1. All subjects had previously participated in similar experiments at the Copenhagen Muscle Research Centre (CMRC) and were familiar with all of the testing procedures. 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 study conformed to the Declaration of Helsinki.
Experimental design
As part of preliminary examinations approximately 2 months prior to 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). Maximal O2 uptake (O2,max) averaged 56 ± 2 ml kg-1 min-1 breathing air at sea level. Associated peak power output was 300 ± 17 W.
The present study was conducted at altitude after 9 weeks residence at 5260 m at Mt Chacaltaya, Bolivia. During this time, two short expeditions (2-4 days) were carried out to peaks at 6080 (Monte Potosí) and 6500 m (Monte Illimani). The latter expedition took place 3-5 days before the start of the experiments. To facilitate adaptation to the exercise protocol at altitude, at least two incremental exercise tests were carried out during the period of acclimatisation. Subjects remained active throughout their stay at altitude, and despite a 7 kg weight loss over the 9 weeks, maximal normoxic cycling power output at 5260 m was 283 ± 18 W, not significantly different from prior sea level values. The loss of body mass is a common finding in high altitude expeditions and may be an important part of the adaptative process (Rose et al. 1988; Westerterp-Plantenga et al. 1999). In fact, all subjects acclimatised very well to the altitude and, at the moment of the experiments, they were free of signs and symptoms of mountain sickness. Actually, they acclimatised so well that their tolerance to exercise at altitude was similar to that observed in Aymara natives, also measured during the expedition (Wagner et al. 2002).
Subjects performed submaximal and maximal upright cycling exercise at two different levels of blood [Hb]. The first was at the blood [Hb] naturally attained after acclimatisation (referred to as the high haemoglobin condition: [Hb] = 185 ± 5 g l-1; haematocrit = 52 ± 1 %). Between 2 and 4 days later, the same exercise protocol was repeated 30 min after the withdrawal of 1.00 ± 0.06 l of blood and immediate replacement by an equal volume of 6 % Dextran 70 solution (Macrodex, Pharmalink AB, Spanga, Sweden), referred to as the low haemoglobin condition. The latter resulted in normovolaemic haemodilution as determined by blood volume assessment with Indocyanine Green (ICG, Akorn Inc., IL, USA; Haller et al. 1993) (5.40 ± 0.31 l before and 5.41 ± 0.33 l after blood removal). With haemodilution, the blood [Hb] and haematocrit dropped similarly by about 24 %, to 142 ± 6 g l-1 and 39 ± 1 %, respectively: values that were similar to those observed at sea level, before the expedition. At the end of the low haemoglobin experiments, the previously removed whole blood was reinfused to the subject.
Experimental preparation
Following local anaesthesia (2 % lidocaine), an 18 gauge catheter (Hydrocath, Ohmeda, Swindon, UK) was inserted percutaneously using the Seldinger technique into either the right or left femoral vein. The catheter was inserted 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, USA) was then inserted 3 cm below the inguinal ligament and advanced proximally 10 cm into the same femoral vein. An 18 gauge catheter was also 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 minimise the risk of movement or creasing. An additional catheter was placed in a vein in the left forearm for the injection of Indocyanine Green. Following catheter placement, the subjects rested in the supine position for 30 min prior to the exercise test.
Exercise protocol
Two exercise levels were undertaken - submaximal (120 W) and maximal exercise - both on a cycle ergometer (Monark 824 E, Valberg, Sweden), as follows. Thirty minutes after catheterization, subjects sat on the cycle ergometer and breathed room air (408 mmHg, PI,O2 = 75-76 mmHg) for 5 min before resting measurements were made (Fig. 1). Subjects then cycled at 120 ± 4 W, the highest intensity they could tolerate for 10 min when exercising in acute hypoxia previously at sea level. Measurements were made at 6 and 10 min. Subsequently, after resting for about 10 min, 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. Measurements were repeated, after which, at the same workload, subjects were switched to 55 % O2 in nitrogen, giving a PI,O2 of about 200 mmHg. After 2 min at this PI,O2, a further set of measurements was made, and finally the workload was increased as tolerated to a new maximal value, with measurements taken again.
 |
View larger version [in this window] [in a new window] |
|
|
Figure 1. Experimental protocol Vertical arrows indicate the time points at which measurements were performed. | ||
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, USA) and averaged every 15 s. Gases with known O2 and CO2 concentrations (micro-Scholander) were used for gas analyser calibration before every test. During submaximal exercise the O2 values obtained during the last four minutes were averaged. During the incremental exercise the highest O2 value recorded during any single 15 s interval was taken as the O2,max.
Blood flow
Femoral venous blood flow (i.e. leg blood flow, LBF) was measured in the femoral vein by constant-infusion thermodilution, as described in detail elsewhere (Andersen et al. 1985). 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, USA) via thermistors connected to the data acquisition system (MacLab 16/s ADInstruments, Sydney, Australia). Infusate temperature was measured with a thermistor set in a flow-through chamber (model 93-505, Edslab) connected to the venous catheter. At rest, saline infusions were continued for at least 60 s, while during exercise 15-20 s long infusions were used until femoral vein temperature had stabilised at its new lower value. Blood flow was calculated on thermal balance principles, as detailed by Andersen et al. (1985). Resting blood flow was measured in triplicate and averaged. During submaximal exercise, blood flow measurements were performed in duplicate at both 6 and 9 min. The reported submaximal values represent the average of the four measurements, as there was no difference in the flows at the two times. At peak effort, the measurements were made within 1 min of exhaustion. When possible, duplicate measurements of LBF (and femoral arteriovenous O2 differences: see below) were made during peak exercise.
Blood pressure and heart rate
Arterial blood pressure was monitored continuously with a disposable transducer (T100209A, Baxter, Unterschleissheim, Germany) placed at the level of the inguinal ligament. A three-lead electrocardiogram was measured and displayed on a monitor during the experimental and recovery phases. Heart rate was obtained either from the pressure curve or from the continuously recorded electrocardiogram signal. The blood pressure transducer and the ECG electrodes were interfaced with a monitor (Dialogue 2000, Danica, Copenhagen, Denmark), which was, in turn, connected to the data acquisition system. Systolic and diastolic arterial pressure 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 with Indocyanine Green (ICG; Akorn Inc, IL, USA) dye-dilution (Dow, 1956). Five to eight milligrams of dye was injected rapidly into the forearm vein followed by a 10 ml flush of isotonic saline. Blood from the femoral artery was withdrawn by a pump (Harvard, 2202A) at 20 ml min-1 through a linear photodensitometer (Waters CO-10, Waters Instruments Inc., Rochester, MN, USA) for measurement of the arterial dye concentration. The withdrawn blood (~20 ml) was reinfused after each determination. The dye curves were displayed on a chart recorder (Gould 8000) and extrapolated with a logarithmic scale based on the exponential decay (downslope) observed from 75 to 50 % of the peak dye concentration to correct for recirculation. Cardiac output was then computed as the ratio of dye injected to the average arterial ICG concentration over the time interval of the curve and expressed in litres per minute. Following each experiment an ICG calibration curve was derived from measuring the deflection from three separate 25 ml blood samples with varying concentrations of ICG.
Blood analysis
Blood haemoglobin concentration ([Hb]) and O2 saturation (SO2) were measured with a co-oximeter (OSM 3 Hemoximeter, Radiometer, Copenhagen, Denmark). PO2, PCO2 and pH were determined with a blood gas analyser (ABL 5, Radiometer, Copenhagen, Denmark) and corrected for measured femoral vein blood temperature. From these values, plasma HCO3- and actual base excess (BE) were determined as described by Siggaard-Andersen (1974). As reduced Hb has a higher buffer capacity than fully oxygenated Hb, arterial BE was adjusted in each blood sample to fully oxygenated Hb (BEadj; Siggaard-Andersen, 1974). Haematocrit was determined by microcentrifugation on triplicate samples. Arterial and femoral venous O2 content (Ca,O2 and Cfv,O2) were computed from the saturation and [Hb], i.e. (1.34[Hb] - SO2) + (0.003 - PO2) Plasma K+ and blood lactate levels were measured with an electrolyte metabolite analyser (EML 105, Radiometer, Copenhagen, Denmark). Plasma noradrenaline and adrenaline concentrations were measured by HPLC with electrochemical detection (Hallman et al. 1978).
Calculations
Arteriovenous [O2] difference (a-vO2,diff) 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 Ca,O2. Leg O2 was calculated as the product of LBF and the a-vO2,diff. Non-leg O2 was computed as the difference between pulmonary O2 and two times leg O2. Leg plasma flow (LPF) was calculated as the product of LBF and (1 - haematocrit). Net lactate release was calculated as the product of LBF and the venous-arterial difference of blood lactate concentration. Potassium release was calculated as the product of LPF and the venous-arterial difference of plasma K+ concentration.
Statistical analysis
Differences in the measured variables among conditions and exercise levels were analysed with two-way ANOVA for repeated measures, with blood [Hb] 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 blood [Hb] 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 ± S.E.M.
|
RESULTS |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Exercise capacity and oxygen uptake
Breathing ambient air at maximal exercise, there were no significant differences in pulmonary or leg O2 or in power output between high and low [Hb] states. This is shown in Fig. 2, upper panels. When 55 % O2 was breathed, the expired gas system failed to indicate O2, but maximal power output (high Hb) was increased from 233 ± 15 W to 283 ± 18 W (P < 0.001). The latter was not significantly different from the maximal work rates at sea level of 300 ± 17 W recorded in Copenhagen prior to the expedition. Maximal leg O2 was also increased by 55 % O2 at both Hb levels (Fig. 2B).
 |
View larger version [in this window] [in a new window] |
|
|
Figure 2. Systemic and leg O2 transport and utilisation Pulmonary | ||
[Hb] and arterial and venous blood gases
The 9 weeks of exposure to altitude increased blood [Hb] by 36 % compared with that at sea level (185 ± 4 vs. 136 ± 5 g l-1, averaging arterial and venous data), while haemodilution returned [Hb] to 142 ± 6 g l-1. Arterial PO2, PCO2 and O2 saturation were all reduced as expected at altitude (Table 1), but haemodilution had no significant effect on these variables at rest or at any exercise level. Since at rest the relative increase in [Hb] exceeded the relative fall in arterial O2 saturation, resting Ca,O2 at altitude (prior to haemodilution) was greater than at sea level (222 ± 7 vs. 180 ± 2 ml l-1, respectively). The isovolaemic reduction of [Hb] led to a 23 % decrease in Ca,O2 (to 171 ± 9 ml l-1). During maximal exercise prior to haemodilution, Ca,O2 breathing air at high [Hb] at 5260 m was reduced to 196 ± 10 ml l-1, because of further desaturation. This still exceeds the value of 189 ± 9 ml l-1 observed during maximal exercise breathing air at sea level before the expedition. Ca,O2 during maximal exercise after haemodilution was 155 ± 8 ml l-1, also due to more desaturation than at rest. Femoral venous PO2 and saturation values during exercise at altitude were not significantly affected by reducing [Hb] (see Table 1), so that femoral venous O2 concentrations were lower following haemodilution. Oxygen extraction - defined as arteriovenous O2 concentration difference divided by arterial O2 concentration - increased as [Hb] was reduced (Fig. 2, lower panels).
Cardiac output, leg blood flow and arterial O2 delivery
At maximal exercise breathing ambient air, cardiac output was the same at both Hb concentrations (Fig. 2C). In fact, except for a minor effect during submaximal exercise, the relationship between cardiac output and work rate was unaffected by [Hb] but slightly increased by FI,O2 (Fig. 2C). In contrast, leg blood flow appeared systematically higher in the low [Hb] condition at any work rate (Fig. 2D). The differences between leg blood flow and cardiac output under the two [Hb] conditions are brought out by directly comparing the two (Fig. 3). Here it is evident that not only is leg flow higher after haemodilution, but it is increasingly so at higher exercise intensities.
 |
View larger version [in this window] [in a new window] |
|
|
Figure 3. Heart rate and stroke volume Heart rate and stroke volume during submaximal and maximal exercise with the blood haemoglobin concentration ([Hb]) attained after 9 weeks of residence at an altitude of 5260 m (squares) and after isovolaemic haemodilution to pre-acclimatisation [Hb] (triangles). The exercises performed while breathing room air at altitude (hypoxia) are represented by filled symbols. Hyperoxic conditions at altitude (FI,O2 = 0.55) are represented by the open symbols. * P < 0.05 when comparing high and low [Hb] conditions. § P < 0.05 for the comparison between hypoxia and hyperoxia at the same exercise intensity and [Hb]. ¶ P < 0.05 for the difference between maximal exercise in hypoxia and maximal exercise in hyperoxia at the same [Hb]. †When comparing maximal exercise conditions with the same arterial O2 content (high [Hb] in hypoxia with low [Hb] in hyperoxia). | ||
Arterial O2 delivery, both to the whole body and (despite higher leg blood flow) to the legs, was reduced at any work rate and FI,O2 after haemodilution (Fig. 2E and F). Taken together with the above-mentioned increases in O2 extraction, these data account for the lack of effect of [Hb] on O2.
Heart rate and stroke volume
The enhancement of cardiac output during submaximal exercise after haemodilution was explained by an increase of heart rate while the stroke volume was similar in both conditions (Fig. 3). At maximal exercise the heart rate response was accentuated with haemodilution, but the stroke volume tended to be lower (P = 0.10; Fig. 3), resulting in similar maximal cardiac output in both conditions. Interestingly, O2 administration close to exhaustion was accompanied by a rapid elevation of heart rate of similar magnitude in both conditions (17-18 beats min-1). The stroke volume, however, mirrored the changes observed in heart rate with hyperoxic breathing, decreasing more markedly in the condition with low [Hb] (P = 0.08). The dependency of stroke volume and heart rate on arterial PO2 is even more evident when comparing maximal exercise conditions with the same arterial O2 content, where hypoxia is associated with the lowest stroke volume and highest heart rate (Fig. 3).
Distribution of cardiac output
Because during maximal exercise cardiac output was unaffected by haemodilution while leg blood flow increased, perfusion of the rest of the body was reduced, from 6.2 ± 0.2 l min-1 (high [Hb]) to 4.5 ± 0.8 l min-1 (low [Hb]) (P = 0.07). In addition, non-leg blood flow during maximal exercise in the high Hb condition was substantially increased by hyperoxic breathing, to 8.4 ± 1.1 l min-1.
Mean arterial pressure, systemic vascular conductance and leg vascular conductance
During submaximal exercise, mean arterial pressure was reduced and total systemic vascular conductance was increased after haemodilution (Fig. 4). No differences in pressure or conductance were seen at maximal exercise, however, at either FI,O2. Leg vascular conductance, on the other hand, tended to be higher after haemodilution under all conditions (Fig. 4).
 |
View larger version [in this window] [in a new window] |
|
|
Figure 4. Arterial pressure and vascular conductance Mean arterial pressure (MAP), systemic vascular conductance (Sys VC) and leg vascular conductance (LVC) during submaximal and maximal exercise with the blood haemoglobin concentration ([Hb]) attained after 9 weeks of residence at an altitude of 5260 m (squares) and after isovolaemic haemodilution to pre-acclimatisation [Hb] (triangles). The exercises performed while breathing room air at altitude (hypoxia) are represented by filled symbols. Hyperoxic conditions at altitude (FI,O2 = 0.55) are represented by the open symbols. *P < 0.05 when comparing high and low [Hb] conditions. ¶P < 0.05 for the difference between maximal exercise in hypoxia and maximal exercise in hyperoxia at the same [Hb]. | ||
Catecholamines
The relationships between arterial adrenaline and noradrenaline levels and work rate are shown under all conditions in Fig. 5. In both cases there is a tendency towards higher concentrations at any work rate after haemodilution (P = 0.07, adrenaline, and P = 0.05, noradrenaline, respectively) but the high variance and small differences preclude definite conclusions. However, there is a single, close, linear relationship between noradrenaline levels and both cardiac output and leg blood flow over all conditions (several exercise intensities, two Hb levels and both FI,O2 values), also shown in Fig. 5. In addition, leg vascular conductance was found to relate closely to arterial noradrenaline concentration at all these conditions.
 |
View larger version [in this window] [in a new window] |
|
|
Figure 5. Plasma catecholamine responses and regulation of cardiac output and leg blood flow Upper panels , plasma arterial adrenaline and noradrenaline (NA) concentrations during submaximal and maximal exercise with the blood haemoglobin concentration ([Hb]) attained after 9 weeks of residence at an altitude of 5260 m (squares) and after isovolaemic haemodilution to pre-acclimatisation [Hb] (triangles). The exercises performed while breathing room air at altitude (hypoxia) are represented by filled symbols. Hyperoxic conditions at altitude (FI,O2 = 0.55) are represented by the open symbols. *P < 0.05 when comparing high and low [Hb] conditions. Middle panels , relationship between two-leg blood flow (2-LBF) and cardiac output with the arterial concentration of noradrenaline. Lower panel , relationship between leg vascular conductance (LVC) and the arterial concentration of noradrenaline. | ||
Arterial potassium concentrations
Arterial potassium levels increased in close proportion to work rate (r = 0.99, P < 0.001), and in turn, both cardiac output and leg blood flow were linearly related to potassium levels (r = 0.97 and r = 0.92, P < 0.01) over all conditions. Moreover, leg vascular conductance was closely related to arterial potassium concentration (r = 0.81, P < 0.05).
Arterial blood lactate
Arterial blood lactate concentration was higher during submaximal exercise with reduced blood [Hb] than it was in the high blood [Hb] condition (6.2 ± 1.0 and 4.9 ± 0.6 mmol l-1, respectively, P < 0.05). In contrast, similar blood lactate concentrations were attained at maximal exercise regardless of blood [Hb].
|
DISCUSSION |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The principal findings of this study are as follows. In lowlanders well acclimatised to 5260 m, acute isovolaemic haemodilution (sufficient to lower the elevated [Hb] to prior sea level values) has no effect on maximal exercise capacity, oxygen uptake or cardiac output. Despite slightly higher leg blood flow, O2 delivery is lower when [Hb] is low, and thus O2 is maintained by greater O2 extraction. At both [Hb] levels, maximal O2 and work rate are increased by giving 55 % O2 to eliminate hypoxia, demonstrating that limitation of maximal O2 while breathing ambient air at 5260 m is due to limited O2 transport and not lack of muscular oxidative capacity. While the cardiac output-work rate relationship is essentially independent of both [Hb] and FI,O2, leg blood flow is systematically greater when [Hb] is reduced. Flows are tightly correlated to both arterial noradrenaline and potassium concentrations.
Effect of [Hb] on maximal work capacity at altitude
This study confirms and extends the work of others showing that acute reduction of [Hb] in previously polycythaemic highlanders (Tufts et al. 1985; Winslow et al. 1985) or lowlanders acclimatised to altitude (Sarnquist et al. 1986; Schaffartzik et al. 1993) does not affect maximal exercise capacity. Although a greater elevation in blood [Hb] concentration was observed and a substantially greater haemodilution (24 vs. 13 %) was induced in our study, our findings essentially agree with those of Sarnquist et al. (1986) and Schaffartzik et al. (1993). Sarnquist et al. (1986) reported similar performance and O2 during exercise at altitude after isovolaemic haemodilution in four experienced climbers whose haematocrits were lowered from 58 to 51 %. Schaffartzik et al. (1993) observed similar O2, leg O2 and exercise capacity during maximal exercise in hypoxia before and after reducing blood [Hb] in humans acclimatised to 3800 m (Schaffartzik et al. 1993). What the present study adds to prior knowledge is that this lack of effect is seen even when maximal O2 is shown to be limited by O2 supply. Thus prior work has not established such O2 dependency. Accordingly, one explanation of previous findings could have been that maximal O2 was limited by muscular oxidative capacity, not O2 supply, in which case manipulations of the O2 transport chain would not have been expected to have any effect on exercise capacity.
Theoretical work has suggested that at high altitude, maximal O2 will become insensitive to [Hb] because any gains in convective circulatory O2 transport from polycythaemia will be offset by corresponding decrements in diffusive transport at the lungs and muscle (Wagner, 1993). Given the actual data of the present study, this theoretical analysis can be applied to ask whether the measured effects of altered [Hb] during maximal exercise are in line with what would be predicted. Indeed, when the muscle O2 transport conductance required to explain the femoral venous data at high [Hb] is applied to the conditions of reduced [Hb], the predicted O2,max at low [Hb] is 2.18 l min-1, which is close to the measured value of 2.05 l min-1. This slight over-prediction of maximal O2 could be due to the fact that [Hb] is known to affect muscle O2 transport conductance, as shown by Hogan et al. (1991). Thus, with reduced [Hb], one would expect a lower conductance for O2, even in the same muscle circulatory bed. However, combining the results obtained in this study with our unpublished observations, it can be shown that there is little or no effect of [Hb] on muscle O2 diffusion capacity (slope of the relationship between O2,max and mean capillary PO2, which ranged between 36 and 40 ml min-1 mmHg-1 during exercise at altitude (Fig. 6). Probably, the increase in blood flow to working muscles after haemodilution might allow recruitment of additional muscle capillaries to stabilise diffusive transport in exercising muscle and, therefore, leg O2,max is maintained despite reduced convective O2 transport. It appears that O2,max is reaching a true maximum under control conditions breathing high O2, as O2 failed to increase despite an increase in blood PO2 (see the arrow in Fig. 6).
 |
View larger version [in this window] [in a new window] |
|
|
Figure 6. Muscle O2 diffusion capacity A, relationship between leg | ||
When the results of the present and prior studies are taken together with the observations that species that have long been resident at high altitude (Tibetans, llama) do not have an especially high [Hb], it is reasonable to postulate that the polycythaemia of altitude does not offer any evolutionary advantage (Winslow, 1988). Perhaps, polycythaemia at altitude simply reflects general activation of the erythropoietin system in response to presumed renal tissue hypoxia, a system that may have developed primarily to counter normoxic anaemia. At sea level, because diffusion limitation in the lungs is less of a problem than at altitude (West & Wagner, 1980), convective O2 transport gains from increased [Hb] would outweigh any decrements from diffusion limitation, at the lungs at least.
At altitude, haemodilution has been reported to improve mental function in polycythaemic mountaineers (Sarnquist et al. 1986). In addition, pulmonary gas exchange can also be ameliorated with haemodilution, through a reduction of the heterogeneity in the ventilation/perfusion distribution (Cruz et al. 1979; Deem et al. 1999). In cases of severe polycythaemia, haemodilution may result in better tissue oxygenation. For example, haemodilution at sea level may increase cerebral flow without any significant enhancement of O2 delivery (Henriksen et al. 1981). Thus, an important question still to be resolved is if any physiological advantage can be obtained with the elevation of blood [Hb] with altitude acclimatisation. At least two possible benefits can be pointed out. First, a higher blood [Hb] at altitude may result in an improvement in endurance capacity (Ekblom et al. 1972; Woodson et al. 1978; Horstman et al. 1980). In the present study, endurance capacity was evaluated indirectly, using the lactate response to a constant-intensity submaximal exercise. Under standardised conditions, a higher blood lactate concentration during submaximal cycling (Schabort et al. 2000) or running (Farrell et al. 1979) implies reduced endurance capacity. The fact that during submaximal exercise the reduction of blood [Hb] was associated with a greater blood lactate concentration, lactate release, heart rate and catecholamine concentrations strongly indicates that haemodilution decreases endurance capacity at altitude. Another possible advantage conferred by the increase in blood [Hb] with altitude acclimatisation is a greater O2 delivery to tissues other than the contracting skeletal muscles at maximal exercise, as shown in the present study.
Regulation of cardiac output during exercise: role of [Hb]
There is much controversy over how cardiac output is regulated during exercise at altitude, especially during maximal exercise after acclimatisation. In general, it is found that after acclimatisation, the cardiac output-oxygen uptake relationship at altitude overlies the sea level relationship, but does not proceed to as high O2 or cardiac output values. Thus, maximal cardiac output is reduced (Pugh et al. 1964; Saltin et al. 1968; Grover et al. 1976; Sutton et al. 1988). Several possible hypotheses can be advanced (Wagner, 2000), but the hypothesis testable in the present study is that the higher viscosity from polycythaemia at altitude reduces maximal cardiac output. Figure 2C provides good evidence that this is unlikely: maximal cardiac output breathing ambient air was not different at [Hb] of 185 and 142 g l-1. Furthermore, with the high [Hb], when hypoxia was eliminated acutely by breathing 55 % O2, maximal cardiac output increased immediately to 23.6 ± 1.4 l min-1 (with maximal work rate and O2 increasing in parallel). These are similar to sea level normoxic maximal values for the same subjects of 23.1 ± 0.9 l min-1 measured when [Hb] was 13.8 g l-1. Had viscosity been the determining factor, such an increase should not have been seen. This observation would also appear to rule out reduced blood volume as the primary factor in the low maximal cardiac output.
Additional insight on cardiac output regulation comes from Fig. 2C. Thus, over the range of exercise at 5260 m, over both [Hb] levels, and over both FI,O2 values, the relationship between cardiac output and power output follows an essentially single linear path, suggesting that maximal cardiac output follows imposed work rate no matter how elements of the O2 transport chain are manipulated. In contrast, Fig. 2E and F shows from the same data that O2 delivery can vary widely over a very narrow range of power output, which suggests that O2 delivery is not tightly regulated to exercise requirements. These observations fit with other data, obtained from the same subjects during the present expedition, but reported elsewhere (Boushel et al. 2001), on the effects of parasympathetic blockade on maximal cardiac output. While the reduced maximal heart rate at 5260 m was increased to sea level values by such blockade, neither maximal power output (and O2,max) nor maximal cardiac output was affected. Thus the cardiac output-work rate relationship was not affected by blockade, and the reduced maximal cardiac output at altitude could not be ascribed to high parasympathetic tone.
Whether cardiac output is set depending on exercise intensity or the other way around cannot be specified from our results. Both feed-forward and feedback mechanisms could potentially couple cardiac output to exercise intensity. However, neither exercise with curarization, an experimental procedure that enhances the command drive from the central nervous system (Secher et al. 1988), nor epidural anaesthesia, which attenuates the sensory feedback, showed any effect on the cardiac output-exercise intensity relationship (Strange et al. 1993; Kjaer et al. 1999). Exercise intensity can modulate cardiac output through its influence on the venous return and preload. The pumping action of the contracting skeletal muscles compressing the veins draining the legs, or muscle pump, is the major mechanism contributing to the venous return in humans during upright exercise (Janicki et al. 1996). The preload may change depending on the regional distribution of circulating volume. The fact that stroke volume was reduced and muscular vasodilatation was increased during maximal exercise after haemodilution suggests that the preload could have been lower after haemodilution, probably due to a greater distribution of the circulating volume to the legs. Even though, maximal cardiac output was similar in both conditions, due to the compensatory elevation of maximal heart rate after haemodilution. Stroke volume at maximal exercise was also attenuated by hyperoxia, probably due to the reduction of the parasympathetic tone with oxygenation and the subsequent enhancement of the chronotropic response to exercise (Boushel et al. 2001), inasmuch as with a similar venous return, stroke volume is reduced if heart rate goes up.
The fact that the switch to hyperoxic breathing allowed subjects to continue exercise, and even increase exercise intensity and cardiac output, demonstrates that the mechanism limiting maximal cardiac output in chronic hypoxia is O2 dependent and of fast response. The rapidity at which the effect of hypoxia can be counteracted just by increasing Pa,O2 is more compatible with a temporary change either in the neuroendocrine regulation of the cardiovascular function or the activity of the central nervous system with hypoxia, rather than a consequence of morphological or structural changes elicited by chronic hypoxia in the heart or the cardiovascular system. For example, hypoxia could have limited maximal cardiac output, acting on the central nervous system by altering the recruitment pattern of motoneurones and, therefore, reducing the maximal exercise intensity attainable, or by a direct depressing effect on the cardiovascular nuclei. The latter is supported by the fact that fatigue occurred at similar Pa,O2 values, in spite of markedly lower Ca,O2 after isovolaemic haemodilution.
Although severe hypoxia might have a negative inotropic effect (Allen & Orchard, 1987), which could have been also responsible for the decrease in maximal cardiac output observed with chronic hypoxia, a direct depression of myocardial function by hypoxia seems unlikely. This is because an increase in cardiac output would have had to be observed with the switch to hyperoxic breathing at the load that produced exhaustion during exercise in chronic hypoxia. However, this was not the case. In addition, no impairment of left ventricular function has been reported in healthy humans at similar (Cargill et al. 1995) or even greater levels of hypoxia (Suarez et al. 1987; Kjaer et al. 1999).
Although our results show that cardiac output is closely related to exercise intensity, it is worth mentioning that there is still some margin for the influence of other possible regulators which can evoke small changes in cardiac output, in the presence of an altered exercise intensity. One situation is during submaximal exercise, where in agreement with previous work in the area we have found an increase in cardiac output to compensate for the reduction in [Hb], such that systemic O2 delivery was maintained (Hartley et al. 1973; Ekblom et al. 1975). The latter supports the classical concept that during submaximal exercise cardiac output is regulated depending on Ca,O2 (see Calbet, 2000, for review). At higher exercise intensities, however, Pa,O2 may play a greater role. This is supported by the fact that when the two conditions that had the same Ca,O2 were compared at maximal exercise, i.e. high [Hb] at room air and low [Hb] with hyperoxia, cardiac output was lower during hypoxia.
Regulation of exercising muscle blood flow: role of [Hb]
In contrast to lack of effect of [Hb] on cardiac output, leg blood flow and leg vascular conductance were both increased systematically after haemodilution, as shown above. There were strikingly close correlations between leg blood flow and both plasma noradrenaline and potassium levels that show in each case a single relationship over all exercise, [Hb] and FI,O2 levels. The correlation with noradrenaline does not suggest cause and effect because this compound is a vasoconstrictor in muscle. Thus higher noradrenaline levels at any given work rate or FI,O2 would, if anything, be expected to reduce muscle blood flow, and yet the opposite occurred. Probably, metabolic vasodilating factors overrode vasoconstricting sympathetic activity during exercise with reduced blood [Hb] (Hansen et al. 2000). The higher noradrenaline levels may therefore be the result of putatively lower muscle tissue PO2 values since the lower [Hb] value is associated with lower O2 delivery and greater extraction (Fig. 2F and H). However, leg noradrenaline release was similar in both conditions. Had noradrenaline clearance remained unchanged, then the increase in the noradrenaline response after haemodilution would reflect a greater level of sympathetically mediated vasoconstriction in other vascular beds. A competition for O2 between respiratory and skeletal muscles has been shown to occur during maximal exercise at sea level (Harms et al. 1997) and, probably, this competition is accentuated during exercise at altitude. In fact, during exercise at extreme altitudes, many climbers complain of dimming of vision and dyspnoea as opposed to leg fatigue. As mentioned above, our subjects reported increased fatigue and difficulty in completing the submaximal exercise bouts after haemodilution. A possible explanation is an accentuated mismatch between respiratory muscle O2 demand and supply after haemodilution due to the reduction of convective and O2 transport to the respiratory muscles. This study supports such a possibility since haemodilution was accompanied by reduction of the difference between cardiac output and leg blood flow, i.e. the amount of blood flow left to perfuse tissues other than the leg muscles. Even though O2,max and maximal exercise capacity do not improve with polycythaemia, a mild increase in haematocrit could be advantageous in providing greater O2 delivery to non-contracting tissues and possibly increasing exercise tolerance. However, the optimal haematocrit for exercise performance at altitude remains to be determined.
The tight relationship between plasma potassium levels and leg blood flow and vascular conductance would appear to be directionally compatible with a cause-and-effect relationship, although the present data cannot of course establish that. Potassium release could facilitate blood flow supply to working muscles by acting at different levels: locally, by eliciting muscular vasodilatation (Skinner & Powell, 1967; Hilton et al. 1978) and by triggering cardiovascular reflexes on stimulation of III and IV muscle afferents (MacLean et al. 2000). In addition, the K+ release from the active muscles may act on the central chemoreceptors increasing ventilation and the sympathetic drive to the heart and muscles (Marshall, 1998), which is in accordance with the close relationship observed in this study between arterial plasma [K+] and cardiac output.
In summary, this study shows that in acclimatised lowlanders, acutely and isovolaemically returning the high [Hb] to normal sea level values has no effect on maximal exercise capacity or O2. This is under conditions of known O2 supply limitation of maximal O2 at 5260 m above sea level, ruling out mitochondrial oxidative capacity limits as the explanation for the lack of effect of [Hb]. The findings are compatible with theoretical predictions and suggest the hypothesis that the polycythaemic response to altitude is not of adaptive value to maximal exercise at altitude. Maximal cardiac output is also unaffected by changes in [Hb], suggesting that the reduced maximal cardiac output at altitude is not caused by higher viscosity associated with the high [Hb]. Leg blood flow is, however, somewhat increased when [Hb] is lowered, and in a manner that correlates closely with circulating potassium and catecholamine levels, suggesting that the potentially reduced O2 availability may stimulate a feedback system resulting in metabolic control of muscle vascular tone that acts to preserve O2 transport to the mitochondria and thus oxygen uptake.
|
REFERENCES |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
| ALLEN, D. G. & ORCHARD, C. H. (1987). Myocardial contractile function during ischemia and hypoxia. Circulation Research 60, 153-168 | [Abstract] |
| ANDERSEN, P., ADAMS, R. P., SJOGAARD, G., THORBOE, A. & SALTIN, B. (1985). Dynamic knee extension as model for study of isolated exercising muscle in humans. Journal of Applied Physiology 59, 1647-1653 | [Medline] |
| BEALL, C. M., BRITTENHAM, G. M., STROHL, K. P., BLANGERO, J., WILLIAMS-BLANGERO, S., GOLDSTEIN, M. C., DECKER, M. J., VARGAS, E., VILLENA, M., SORIA, R., ALARCON, A. M. & GONZALES, C. (1998). Hemoglobin concentration of high-altitude Tibetans and Bolivian Aymara. American Journal of Physical Anthropology 106, 385-400 | [Medline] |
| BENDER, P. R., GROVES, B. M., MCCULLOUGH, R. E., MCCULLOUGH, R. G., HUANG, S. Y., HAMILTON, A. J., WAGNER, P. D., CYMERMAN, A. & REEVES, J. T. (1988). Oxygen transport to exercising leg in chronic hypoxia. Journal of Applied Physiology 65, 2592-2597 | [Abstract] |
| BOUSHEL, R., CALBET, J. A., RADEGRAN, G., SONDERGAARD, H., WAGNER, P. D. & SALTIN, B. (2001). Parasympathetic neural activity accounts for the lowering of exercise heart rate at high altitude. Circulation 104, 1785-1791 | [Abstract/Full Text] |
| CALBET, J. A. (2000). Oxygen tension and content in the regulation of limb blood flow. Acta Physiologica Scandinavica 168, 465-472 | [Medline] |
| CARGILL, R. I., KIELY, D. G. & LIPWORTH, B. J. (1995). Left ventricular systolic performance during acute hypoxemia. Chest 108, 899-902 | [Abstract] |
| CRUZ, J. C., DIAZ, C., MARTICORENA, E. & HILARIO, V. (1979). Phlebotomy improves pulmonary gas exchange in chronic mountain polycythemia. Respiration 38, 305-313 | |
| DEEM, S., HEDGES, R. G., MCKINNEY, S., POLISSAR, N. L., ALBERTS, M. K. & SWENSON, E. R. (1999). Mechanisms of improvement in pulmonary gas exchange during isovolemic hemodilution. Journal of Applied Physiology 87, 132-141 | [Abstract/Full Text] |
| DOW, P. (1956). Estimations of cardiac output and central blood volume by dye dilution. Physiological Reviews 36, 77-102 | |
| EKBLOM, B., GOLDBARG, A. N. & GULLBRING, B. (1972). Response to exercise after blood loss and reinfusion. Journal of Applied Physiology 33, 175-180 | [Medline] |
| EKBLOM, B., HUOT, R., STEIN, E. M. & THORSTENSSON, A. T. (1975). Effect of changes in arterial oxygen content on circulation and physical performance. Journal of Applied Physiology 39, 71-75 | [Medline] |
| FARRELL, P. A., WILMORE, J. H., COYLE, E. F., BILLING, J. E. & COSTILL, D. L. (1979). Plasma lactate accumulation and distance running performance. Medicine and Science in Sports and Exercise 11, 338-344 | |
| FAVIER, R., DESPLANCHES, D., HOPPELER, H., CACERES, E., GRUNENFELDER, A., KOUBI, H., LEUENBERGER, M., SEMPORE, B., TUSCHER, L. & SPIELVOGEL, H. (1996). Hormonal and metabolic adjustments during exercise in hypoxia or normoxia in highland natives. Journal of Applied Physiology 80, 632-637 | [Abstract] |
| GROVER, R. F., LUFSCHANOWSKI, R. & ALEXANDER, J. K. (1976). Alterations in the coronary circulation of man following ascent to 3,100 m altitude. Journal of Applied Physiology 41, 832-838 | [Medline] |
| HALLER, M., AKBULUT, C., BRECHTELSBAUER, H., FETT, W., BRIEGEL, J., FINSTERER, U. & PETER, K. (1993). Determination of plasma volume with indocyanine green in man. Life Sciences 53, 1597-1604 | [Medline] |
| HALLMAN, H., FARNEBO, L. O., HAMBERGER, B. & JOHNSSON, G. (1978). A sensitive method for the determination of plasma catecholamines using liquid chromatography with electrochemical detection. Life Sciences 23, 1049-1052 | [Medline] |
| HANSEN, J., SANDER, M. & THOMAS, G. D. (2000). Metabolic modulation of sympathetic vasoconstriction in exercising skeletal muscle. Acta Physiologica Scandinavica 168, 489-503 | [Medline] |
| HARMS, C. A., BABCOCK, M. A., MCCLARAN, S. R., PEGELOW, D. F., NICKELE, G. A., NELSON, W. B. & DEMPSEY, J. A. (1997). Respiratory muscle work compromises leg blood flow during maximal exercise. Journal of Applied Physiology 82, 1573-1583 | [Abstract/Full Text] |
| HARTLEY, L. H., VOGEL, J. A. & LANDOWNE, M. (1973). Central, femoral, and brachial circulation during exercise in hypoxia. Journal of Applied Physiology 34, 87-90 | [Medline] |
| HENRIKSEN, L., PAULSON, O. B. & SMITH, R. J. (1981). Cerebral blood flow following normovolemic hemodilution in patients with high hematocrit. Annals of Neurology 9, 454-457 | [Medline] |
| HILTON, S. M., HUDLICKA, O. & MARSHALL, J. M. (1978). Possible mediators of functional hyperaemia in skeletal muscle. Journal of Physiology 282, 131-147 | [Abstract] |
| HOGAN, M. C., BEBOUT, D. E. & WAGNER, P. D. (1991). Effect of hemoglobin concentration on maximal O2 uptake in canine gastrocnemius muscle in situ. Journal of Applied Physiology 70, 1105-1112 | [Abstract] |
| HORSTMAN, D., WEISKOPF, R. & JACKSON, R. E. (1980). Work capacity during 3-wk sojourn at 4,300 m: effects of relative polycythemia. Journal of Applied Physiology 49, 311-318 | [Medline] |
| JANICKI, J. S., SHERIFF, D. D., ROBOTHAM, J. L. & WISE, R. A. (1996). Cardiac output during exercise: contributions of the cardiac, circulatory, and respiratory systems. In Handbook of Physiology, section 12, Exercise: Regulation and Integration of Multiple Systems, ed. ROWELL, L. B. & SHEPHERD, J. T., pp. 649-704. American Physiological Society, Bethesda, MD, USA | |
| KJAER, M., HANEL, B., WORM, L., PERKO, G., LEWIS, S. F., SAHLIN, K., GALBO, H. & SECHER, N. H. (1999). Cardiovascular and neuroendocrine responses to exercise in hypoxia during impaired neural feedback from muscle. American Journal of Physiology 277, R76-85 | [Medline] |
| MACLEAN, D. A., IMADOJEMU, V. A. & SINOWAY, L. I. (2000). Interstitial pH, K+, lactate, and phosphate determined with MSNA during exercise in humans. American Journal of Physiology 278, R563-571 | |
| MARSHALL, J. M. (1998). Chemoreceptors and cardiovascular control in acute and chronic systemic hypoxia. Brazilian Journal of Medical and Biological Research 31, 863-888 | |
| PUGH, L. G. C. E., GILL, M. B., LAHIRI, S., MILLEDGE, J. S., WARD, M. P. & WEST, J. B. (1964). Muscular exercise at great altitudes. Journal of Applied Physiology 19, 431-440 | |
| RICHARDSON, T. Q. & GUYTON, A. C. (1959). Effects of polycythemia and anemia on cardiac output and other circulatory factors. American Journal of Physiology 197, 1167-1170 | |
| ROSE, M. S., HOUSTON, C. S., FULCO, C. S., COATES, G., SUTTON, J. R. & CYMERMAN, A. (1988). Operation Everest. II: Nutrition and body composition. Journal of Applied Physiology 65, 2545-2551 | [Abstract] |
| SALTIN, B., GROVER, R. F., BLOMQVIST, C. G., HARTLEY, L. H. & JOHNSON, R. L. (1968). Maximal oxygen uptake and cardiac output after two weeks at 4300 m. Journal of Applied Physiology 25, 400-409 | |
| SARNQUIST, F. H., SCHOENE, R. B., HACKETT, P. H. & TOWNES, B. D. (1986). Hemodilution of polycythemic mountaineers: effects on exercise and mental function. Aviation, Space and Environmental Medicine 57, 313-317 | [Medline] |
| SCHABORT, E. J., KILLIAN, S. C., ST CLAIR GIBSON, A., HAWLEY, J. A. & NOAKES, T. D. (2000). Prediction of triathlon race time from laboratory testing in national triathletes. Medicine and Science in Sports and Exercise 32, 844-849 | [Medline] |
| SCHAFFARTZIK, W., BARTON, E. D., POOLE, D. C., TSUKIMOTO, K., HOGAN, M. C., BEBOUT, D. E. & WAGNER, P. D. (1993). Effect of reduced hemoglobin concentration on leg oxygen uptake during maximal exercise in humans [editorial]. Journal of Applied Physiology 75, 491-498 | [Abstract] |
| SECHER, N. H., KJAER, M. & GALBO, H. (1988). Arterial blood pressure at the onset of dynamic exercise in partially curarized man. Acta Physiologica Scandinavica 133, 233-237 | [Medline] |
| SIGGAARD-ANDERSEN, O. (1974). The Acid-Base Status of Blood. Munksgaard, Copenhagen | |
| SKINNER, N. S. JR & POWELL, W. J. JR (1967). Action of oxygen and potassium on vascular resistance of dog skeletal muscle. American Journal of Physiology 212, 533-540 | [Medline] |
| STRANGE, S., SECHER, N. H., PAWELCZYK, J. A., KARPAKKA, J., CHRISTENSEN, N. J., MITCHELL, J. H. & SALTIN, B. (1993). Neural control of cardiovascular responses and of ventilation during dynamic exercise in man. Journal of Physiology 470, 693-704 | [Abstract] |
| SUAREZ, J., ALEXANDER, J. K. & HOUSTON, C. S. (1987). Enhanced left ventricular systolic performance at high altitude during Operation Everest II. American Journal of Cardiology 60, 137-142 | [Medline] |
| SUTTON, J. R., REEVES, J. T., WAGNER, P. D., GROVES, B. M., CYMERMAN, A., MALCONIAN, M. K., ROCK, P. B., YOUNG, P. M., WALTER, S. D. & HOUSTON, C. S. (1988). Operation Everest II: oxygen transport during exercise at extreme simulated altitude. Journal of Applied Physiology 64, 1309-1321 | [Abstract] |
| TUFTS, D. A., HAAS, J. D., BEARD, J. L. & SPIELVOGEL, H. (1985). Distribution of hemoglobin and functional consequences of anemia in adult males at high altitude. American Journal of Clinical Nutrition 42, 1-11 | [Abstract] |
| WAGNER, P. D. (1993). Algebraic analysis of the determinants of VO2,max. Respiration Physiology 93, 221-237 | [Medline] |
| WAGNER, P. D. (2000). Reduced maximal cardiac output at altitude - mechanisms and significance. Respiration Physiology 120, 1-11 | [Medline] |
| WAGNER, P. D., ARAOZ, M., BOUSHEL, R., CALBET, J. A., JESSEN, B., RADEGRAN, G., SPIELVOGEL, H., SONDEGAARD, H., WAGNER, H. & SALTIN, B. (2002). Pulmonary gas exchange and acid-base state at 5,260 m in high-altitude Bolivians and acclimatized lowlanders. Journal of Applied Physiology 92, 1393-1400 | [Abstract/Full Text] |
| WEISER, M. G., FETTMAN, M. J., VAN HOUTEN, D., JOHNSON, L. & GARRY, F. (1992). Characterization of erythrocytic indices and serum iron values in healthy llamas. American Journal of Veterinary Research 53, 1776-1779 | [Medline] |
| WEST, J. B. & WAGNER, P. D. (1980). Predicted gas exchange on the summit of Mt. Everest. Respiration Physiology 42, 1-16 | [Medline] |
| WESTERTERP-PLANTENGA, M. S., WESTERTERP, K. R., RUBBENS, M., VERWEGEN, C. R., RICHELET, J. P. & GARDETTE, B. (1999). Appetite at 'high altitude' [Operation Everest III (Comex-'97)]: a simulated ascent of Mount Everest. Journal of Applied Physiology 87, 391-399 | [Abstract/Full Text] |
| WINSLOW, R. M. (1988). Optimal hematologic variables for oxygen transport, including P50, hemoglobin cooperativity, hematocrit, acid-base status, and cardiac function. Biomaterials, Artificial Cells and Artificial Organs 16, 149-171 | |
| WINSLOW, R. M., MONGE, C. C., BROWN, E. G., KLEIN, H. G., SARNQUIST, F., WINSLOW, N. J. & MCKNEALLY, S. S. (1985). Effects of hemodilution on O2 transport in high-altitude polycythemia. Journal of Applied Physiology 59, 1495-1502 | [Medline] |
| WOODSON, R. D., WILLS, R. E. & LENFANT, C. (1978). Effect of acute and established anemia on O2 transport at rest, submaximal and maximal work. Journal of Applied Physiology 44, 36-43 | [Medline] |
Acknowledgements
Special thanks are given to Birgitte Jessen, Harrieth Wagner, Carsten Nielsen and Karin Hansen for their excellent technical assistance, and George Ordway for his insightful comments. In particular, we grateful for the invaluable help given by Professor Carlos Aguirre from the Academia Nacional de Ciencias de Bolivia and Dr Pedro Miranda, Director of the Laboratorio de Cósmica Física at Chacaltaya, where the experiments were conducted. All the help and support provided by Dr Mauricio Araoz and Dr Hilde Spielvogel is also greatly acknowledged. This study was supported mainly by a grant from the Danish National Research Foundation (504-14). Additional funding was provided by the Carlsberg Foundation and the Copenhagen Muscle Research Centre. J.A.L.C. was on leave from the Department of Physical Education at the University of Las Palmas de Gran Canaria.
This article has been cited by other articles:
|
|
 |
|
  C. Lundby, P. Robach, R. Boushel, J. J. Thomsen, P. Rasmussen, M. Koskolou, and J. A. L. Calbet Does recombinant human Epo increase exercise capacity by means other than augmenting oxygen transport? J Appl Physiol, August 1, 2008; 105(2): 581 - 587. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Amann and J. A. L. Calbet Convective oxygen transport and fatigue J Appl Physiol, March 1, 2008; 104(3): 861 - 870. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Lundby, R. Boushel, P. Robach, K. Moller, B. Saltin, and J. A. L. Calbet During hypoxic exercise some vasoconstriction is needed to match O2 delivery with O2 demand at the microcirculatory level J. Physiol., January 1, 2008; 586(1): 123 - 130. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Amann, L. M. Romer, A. W. Subudhi, D. F. Pegelow, and J. A. Dempsey Severity of arterial hypoxaemia affects the relative contributions of peripheral muscle fatigue to exercise performance in healthy humans J. Physiol., May 15, 2007; 581(1): 389 - 403. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. A. Basset, D. R. Joanisse, F. Boivin, J. St-Onge, F. Billaut, J. Dore, R. Chouinard, G. Falgairette, D. Richard, and M. R. Boulay Effects of short-term normobaric hypoxia on haematology, muscle phenotypes and physical performance in highly trained athletes Exp Physiol, March 1, 2006; 91(2): 391 - 402. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A L Calbet, R. Boushel, and C. Lundby Comment on Point:Counterpoint "Positive effects of intermittent hypoxia (live high:train low) on exercise performance are/are not mediated primarily by augmented red cell volume" J Appl Physiol, February 1, 2006; 100(2): 749 - 749. [Full Text] [PDF]
|
|
|
|
|
|
S. Keslacy, R. S. Mazzeo, D. A. Giussani, A. S. Thakor, G. Insalaco, M. R. Bonsignore, F. A. Rodriguez, K. S. Mark, C. Reboul, S. Tanguy, et al. Commentary on Point-Co |
