The 'lactate paradox', evidence for a transient change in the course of acclimatization to severe hypoxia in lowlanders.

The metabolic response to exercise at high altitude is different from that at sea level, depending on the altitude, the rate of ascent and duration of acclimatization. One apparent metabolic difference that was described in the 1930s is the phenomenon referred to as the 'lactate paradox'. Acute exposure to hypoxia results in higher blood lactate accumulation at submaximal workloads compared with sea level, but peak blood lactate remain the same. Following continued exposure to hypoxia or altitude, blood lactate accumulation at submaximal work and peak blood lactate levels are paradoxically reduced compared with those at sea level. It has recently been shown, however, that, if the exposure to altitude is sufficiently long, blood lactate responses return to those seen at sea level or during acute hypoxia. Thus, to evaluate the 'lactate paradox' phenomenon in relation to time spent at altitude, five Danish lowland climbers were studied at sea level, during acute exposure to hypoxia (10% O2 in N2) and 1, 4 and 6 weeks after arrival in the basecamp of Mt Everest (approximately 5400 m, Nepal). Basecamp was reached after 10 days of gradual ascent from 2800 m. Peak blood lactate levels were similar at sea level (11.0 +/- 0.7 mmol L-1) and during acute hypoxia (9.9 +/- 0.3 mmol L-1), but fell significantly after 1 week of acclimatization to 5400 m (5.6 +/- 0.5 mmol L-1) as predicted by the 'lactate paradox'. After 4 weeks of acclimatization, peak lactate accumulation (7.8 +/- 1.0 mmol L-1) was still lower compared with acute hypoxia but higher than that seen after 1 week of acclimatization. After 6 weeks of acclimatization, 2 days after return to basecamp after reaching the summit or south summit of Mt Everest, peak lactate levels (10.4 +/- 1.1 mmol L-1) were similar to those seen during acute hypoxia. Therefore, these results suggest that the 'lactate paradox' is a transient metabolic phenomenon that is reversed during a prolonged period of exposure to severe hypoxia of more than 6 weeks.     

Power and peak blood lactate at 5050 m with 10 and 30 s ‘all out’ cycling

Anecdotal observations suggest that the reduction in peak lactate accumulation in blood ([La]_{b peak}) after exhausting exercise, in chronic hypoxia vs. normoxia, may be related to the duration of the exercise protocol, being less pronounced after short supramaximal exercise than after incremental exercise (IE) lasting several minutes. To test this hypothesis, six healthy male Caucasians (age 36.8 ± 7.3, x¯ ± SD) underwent three exercise protocols on a cycle ergometer, at sea level (SL) and after 21 ± 10 days at 5050 m altitude (ALT): (1) 10 s, (2) 30 s ‘all out’ exercise and (3) IE leading to exhaustion in ～20–25 min. ‘Average’ power output (p¯) was calculated for 10 or 30 s ‘all out’; maximal power output (P_max) was determined for IE. Lactate concentration in arterialized capillary blood ([La]_b) was measured at rest and at different times during recovery; the highest [La]_b during recovery was taken as [La]_{b peak}. No significant differences in p¯ were observed between SL and ALT, for either 10 or 30 s ‘all out’ exercise; P_max during IE was significantly lower at ALT than at SL. [La]_{b peak} after 10 s ‘all out’ was unaffected by chronic hypoxia (7.0 ± 0.9 at ALT vs. 6.3 ± 1.8 mmol L^–1 at SL). After 30 s ‘all out’ the [La]_{b peak} decrease, at ALT (10.6 ± 0.6 mmol L^–1) vs. SL (12.9 ± 1.4 mmol L^–1), was only ～50% of that observed for IE (6.7 ± 1.6 mmol L^–1 vs. 11.3 ± 2.8 mmol L^–1). Muscle power output and blood lactate accumulation during short supramaximal exercise are substantially unaffected by chronic hypoxia.     

Substrate utilization in sea level residents during exercise in acute hypoxia and after 4 weeks of acclimatization to 4100 m

To investigate the effect of acclimatization to hypoxia on substrate utilization, eight sea level residents were studied during exercise at the same relative (rel) and absolute (abs) work rate as at sea level (SL), under acute (AH), and after 4 weeks exposure to 4100 m altitude (CH). Carbohydrate (CHO) and fat oxidation during exercise at SL were 2.0 ± 0.2 and 0.3 ± 0.0 g min^?1, respectively. At AH_abs and CH_abs CHO oxidation increased (P < 0.05) to 2.5 ± 0.2 and 2.3 ± 0.1 for CHO, and fat oxidation decreased (P < 0.05) to 0.2 ± 0.01 and 0.2 ± 0.01 g min^?1, respectively. Exercise in AH_rel and CH_rel did not cause a change in the relative CHO and fat oxidation compared with SL, the absolute rate of CHO oxidized being 1.7 ± 0.1 and 1.7 ± 0.02 g min^?1, respectively, and fat oxidation was 0.2 ± 0.02 g min^?1 in AC_rel and 0.3 ± 0.02 g min^?1 in CH_rel. In conclusion, substrate utilization is unaffected by AH and CH, when the work rate is matched to the same relative intensity as at SL.     

The lactate paradox revisited in lowlanders during acclimatization to 4100 m and in high-altitude natives

Chronic hypoxia has been proposed to induce a closer coupling in human skeletal muscle between ATP utilization and production in both lowlanders (LN) acclimatizing to high altitude and high-altitude natives (HAN), linked with an improved match between pyruvate availability and its use in mitochondrial respiration. This should result in less lactate being formed during exercise in spite of the hypoxaemia. To test this hypothesis six LN (22–31 years old) were studied during 15 min warm up followed by an incremental bicycle exercise to exhaustion at sea level, during acute hypoxia and after 2 and 8 weeks at 4100 m above sea level (El Alto, Bolivia). In addition, eight HAN (26–37 years old) were studied with a similar exercise protocol at altitude. The leg net lactate release, and the arterial and muscle lactate concentrations were elevated during the exercise in LN in acute hypoxia and remained at this higher level during the acclimatization period. HAN had similar high values; however, at the moment of exhaustion their muscle lactate, ADP and IMP content and Cr/PCr ratio were higher than in LN. In conclusion, sea-level residents in the course of acclimatization to high altitude did not exhibit a reduced capacity for the active muscle to produce lactate. Thus, the lactate paradox concept could not be demonstrated. High-altitude natives from the Andes actually exhibit a higher anaerobic energy production than lowlanders after 8 weeks of acclimatization reflected by an increased muscle lactate accumulation and enhanced adenine nucleotide breakdown.     

Long-term exposure to intermittent hypoxia results in increased hemoglobin mass,reduced plasma volume,and elevated erythropoietin plasma levels in man

While it is well established that highlanders have optimized their oxygen transport system, little is known about the acclimatization of those who move between different altitudes. The purpose of this study was to establish whether the acclimatization to long-term intermittent hypoxic exposure in members of the Chilean Army who frequently move from sea level to 3,550 m altitude is correlated with acute acclimatization or chronic adaptation to hypoxia. A group of officers was exposed intermittently to hypoxia for about 22 years (OI, officers at intermittent hypoxia) and a group of soldiers for 6 months (SI, soldiers at intermittent hypoxia). Both groups were compared to residents at altitude (RA) and to soldiers at sea level (SL). When compared to SL, we observed an 11% increase in total hemoglobin mass (tHb) as well as a corresponding increase in red cell volume (RCV), hemoglobin concentration and hematocrit in all three groups at altitude. Plasma volume (PV) and blood volume (BV) decreased at altitude but increased when OI and SI returned to sea level. Moreover, intermittent hypoxic exposure of OI and SI resulted in increased plasma erythropoietin (Epo) levels, which peaked on day 2 at high altitude followed by decreasing levels during the successive days, and reaching pre-altitude values in SI even when staying at altitude. In conclusion, with regard to tHb and RCV, the acclimatization to long-term intermittent hypoxia resembles the adaptation to chronic hypoxia, while PV and BV regulation mimicked acclimatization to acute hypoxia. Remarkably, finely controlled regulation of Epo expression still occurs after up to 22 years of weekly exposure to altitude. Electronic Publication     

Erythropoietin concentrations during 10 days of normobaric hypoxia under controlled environmental circumstances

Serum erythropoietin levels (s‐[epo]), haemoglobin concentration ([Hb]), haematocrit (hct), and ferritin concentration ([fer]) were measured in seven healthy male volunteers (20–23 years) exposed continuously to hypoxia (PO₂ 14 kPa) for 10 days. Serum erythropoietin concentration increased significantly from 9.5 ± 3.51 to 33.6 ± 11.64 U L^–1 (P < 0.05) after 2 days of hypoxia. Thereafter, s‐[epo] decreased. However, after 10 days s‐[epo] was 18.7 ± 5.83 U L^–1 which was still increased above the pre‐hypoxia level (P < 0.05). Serum haemoglobin concentration and hct increased over the 10 days of hypoxia, [Hb] from 152 ± 8.9 to 168 ± 9.2 gL^–1 (P < 0.001), and hct from 43 ± 2.4 to 49 ± 2.6% (P < 0.001). Ferritin concentration decreased significantly during the hypoxic exposure from 82 ± 46.9 to 44 ± 31.7 mmol L^–1 after 10 days (P < 0.01). In conclusion, the initial increase of s‐[epo] under controlled normobaric hypoxia was marked, 353%, and levelled off after 5–10 days at 62–97% above normoxia level. There was also a significant increase in [Hb] and hct and a decrease in [fer] after 10 days of exposure to normobaric hypoxia.     

Autonomic nervous control of heart rate at altitude (5050 m)

To investigate possible changes in autonomic regulation of heart rate as a result of acclimatization to high altitude, indexes of autonomic nervous activity were obtained non invasively by spectrum analysis of heart rate variability on five healthy male subjects [age, 31 (SEM 2) years] during a postural change from supine to seated, both at sea level and after 1 month of exposure to an altitude of 5050 m. Heart rate fluctuations at the respiratory frequency (high frequency, HF) are mediated by the parasympathetic system whereas fluctuations at about 0.1 Hz (low frequency, LF) are due to both sympathetic and parasympathetic nervous systems. Maximal heart rate, as measured during an incremental exercise test, decreased from 184 (SEM 5) beats · min^–1 at sea level to 152 (SEM 2) beats · min^–1 at 5050 m. At sea level, the change in posture from supine to seated induced an increase in LF amplitude accompanied by an increase or a decrease in HF amplitude, whereas after 1 month at altitude the HF amplitude decreased in all subjects, with little or no change in LF amplitude. These results indicate a changed strategy of heart rate regulation after acclimatization to high altitude. At sea level, the postural change induced an increase in sympathetic activity in all subjects with different individual vagal responses, whereas at altitude the postural change induced a net decrease in vagal tone in all subjects, with little or no change in sympathetic activity. These results corroborate the reported reduced sensitivity of the heart to adrenergic drive in chronic hypoxia, which may, at least in part, explain the decreased maximal heart rate in altitude-acclimatized human subjects.     

Arterio‐venous differences of blood acid–base status and plasma sodium caused by intense bicycling

After intense exercise muscle may give off hydrogen ions independently of lactate, perhaps by a mechanism involving sodium ions. To examine this possibility further five healthy young men cycled for 2 min to exhaustion. Blood was drawn from catheters in the femoral artery and vein during exercise and at 1‐h intervals after exercise. The blood samples were analysed for pH, blood gases, lactate, haemoglobin, and plasma proteins and electrolytes. Base deficit was calculated directly without using common approximations. The leg blood flow was also measured, thus allowing calculations of the leg’s exchange of metabolites. The arterial blood lactate concentration rose to 14.2 ± 1.0 mmol L^–1, the plasma pH fell to 7.18 ± 0.02, and the base deficit rose 22% more than the blood lactate concentration did. The femoral‐venous minus arterial differences peaked at 1.8 ± 0.2 mmol L^–1 (lactate), –0.24 ± 0.01 (pH), and 4.5 ± 0.4 mmol L^–1 (base deficit), and –2.5 ± 0.7 mmol L^–1 (plasma sodium concentration corrected for volume changes). Thus, near the end of the exercise and for the first 10 min of the recovery period the leg gave off more hydrogen ions than lactate ions to the blood, and sodium left plasma in proportion to the extra hydrogen ions appearing. The leg’s integrated excess release of hydrogen ions of 0.88 ± 0.45 mmol kg^–1 body mass was 67% of the integrated lactate release. Base deficit calculated by the traditional approximate equations underestimated the true value, but the error was less than 10%. We conclude that intense exercise and lactic acidosis may lead to a muscle release of hydrogen ions independent of lactate release, possibly by a Na⁺,H⁺ exchange. Hydrogen ions were largely buffered in the red blood cells.     

Effects of acute moderate hypoxia on anaerobic capacity in endurance-trained runners

While there is some controversy whether anaerobic capacity might be improved after altitude training little is known about changes in anaerobic capacity during hypoxic exposure in highly trained athletes. In order to analyze the effects of acute moderate normobaric hypoxia on anaerobic capacity, 18 male competitive triathletes, middle- and long-distance runners performed 2 supra- treadmill runs with the same speed, one in normoxia and one after 4 h exposure to normobaric hypoxia (FiO₂ 0.15), for estimation of their maximal accumulated oxygen deficit (MAOD) and measurement of peak capillary lactate and peak capillary ammonia concentration. MAOD was not significantly different in normoxia and in moderate hypoxia while time to exhaustion and accumulated O₂ uptake were significantly (P < 0.001) reduced in hypoxia compared to normoxia by 28 and 45%, respectively. The reduction in time to exhaustion was significantly correlated to the decrement in accumulated O₂ uptake (R = 0.730, P = 0.001). In hypoxia, there was a tendency for peak capillary lactate concentration to be decreased compared to normoxia (12.9 ± 2.1 vs. 13.8 ± 2.2 mmol l⁻¹, P = 0.082); peak capillary ammonia concentration was significantly decreased in hypoxia (97 ± 52 vs. 121 ± 44 μmol l⁻¹, P = 0.032). In conclusion, anaerobic capacity is not significantly changed during acute exposure to moderate hypoxia in endurance-trained athletes. The performance reduction during all-out exercise of short duration has to be attributed to the decrement in aerobic capacity.     

Sympathetic neural overactivity in healthy humans after prolonged exposure to hypobaric hypoxia

Acute exposure to hypoxia causes chemoreflex activation of the sympathetic nervous system. During acclimatization to high altitude hypoxia, arterial oxygen content recovers, but it is unknown to what degree sympathetic activation is maintained or normalized during prolonged exposure to hypoxia. We therefore measured sympathetic nerve activity directly by peroneal microneurography in eight healthy volunteers (24 ± 2 years of age) after 4 weeks at an altitude of 5260 m (Chacaltaya, Bolivian Andes) and at sea level (Copenhagen). The subjects acclimatized well to altitude, but in every subject sympathetic nerve activity was highly elevated at altitude vs. sea level (48 ± 5 vs. 16 ± 3 bursts min⁻¹, respectively,   P < 0.05  ), coinciding with increased mean arterial blood pressure (87 ± 3 vs. 77 ± 2 mmHg, respectively,   P < 0.05  ). To examine the underlying mechanisms, we administered oxygen (to eliminate chemoreflex activation) and saline (to reduce cardiopulmonary baroreflex deactivation). These interventions had minor effects on sympathetic activity (48 ± 5 vs. 38 ± 4 bursts min⁻¹, control vs. oxygen + saline, respectively,   P < 0.05  ). Moreover, sympathetic activity was still markedly elevated (37 ± 5 bursts min⁻¹) when subjects were re-studied under normobaric, normoxic and hypervolaemic conditions 3 days after return to sea level. In conclusion, acclimatization to high altitude hypoxia is accompanied by a striking and long-lasting sympathetic overactivity. Surprisingly, chemoreflex activation by hypoxia and baroreflex deactivation by dehydration together could account for only a small part of this response, leaving the major underlying mechanisms unexplained.     

Training-induced increases in sea level V˙O2 m a x and endurance are not enhanced by acute hypobaric exposure

The present study used untrained subjects to examine the effect of acute hypobaric exposure during endurance training on subsequent exercise performance at sea level. Two groups, each of nine subjects, completed 5 weeks of endurance training [cycle ergometer exercise for 45 min, three times per week at a heart rate corresponding to 70% of that achieved at the maximal O₂ consumption (V˙O_{2 max} ) either at sea level or at high altitude] in a hypobaric chamber, under either normobaric [sea level, SL; 750 mmHg (100 kPa) ≈90 m] or hypobaric [altitude, ALT; 554 mmHg (73.4 kPa) ≈ 2500 m] conditions and the changes in SL V˙O_{2 max} , SL endurance time and peak blood lactate during the endurance test compared. While each group showed increases in both SL V˙O_{2 max} (≈12%) and SL endurance time (≈71%), there were no significant differences between the groups [SL V˙O_{2 max} , mean (SE) – SL group: pre-training = 42.4 (3.5), post-training = 46.1 (3.5) ml · kg^?1· min^?1, P < 0.005; ALT group: pre-training = 40.8 (2.6), post-training = 47.2 (3.4) ml · kg^?1· min^?1, P < 0.01; SL endurance time – SL group: pre-training 7.1 (1.5), post-training 11.8 (2.9) min, P < 0.01; ALT group: pre-training = 7.5 (0.6), post-training = 13.3 (1.4) min, P < 0.001]. Peak blood lactate during the endurance test was not altered by either training regimen. It is concluded that acute exposure of untrained subjects to hypobaric hypoxia during endurance training has no synergistic effect on the degree of improvement in either SL V˙O_{2 max} or endurance time.     

Cardiovascular response to exercise in humans following acclimatization to extreme altitude

The purpose of this study was to assess the effects of acclimatization to extreme altitude on the cardiovascular system, using vagal and adrenergic blockade and acute restoration of normoxia during exercise to maximum with one and two legs. Fourteen climbers on an expedition to the Himalayas were studied at a lower base camp (5250 m) following 56–81 days at altitudes between 5250 and 8700 m. After acclimatization, peak heart rate (HR_peak), oxygen uptake (o_2k) and noradrenaline (NA) were similar during maximal one- and two-legged cycling, whereas peak plasma lactate was higher during the one-legged protocol. HR_peak (range 113–168 beats min“¹) was lowest when subjects returned from the higher camps. The degree of partial restoration of HR_peak to more normal values within seconds of 60% 0₂ inhalation (range 5–35 beats min?^l HR_peak increase) was greatest in subjects with low HR_peak. HR responses to /?-l blockade increased as a function of HR_peak and the HR responses to atropine were the least in subjects with high HRpeak- These findings suggest that (a) the reduction in HR_peak is linked to the duration and severity of the hypoxaemia, (b) the degree of restoration of HR_peak with acute normoxia is dependent on the level of attenuation or down-regulation of cardiac sympathetic activation (SNA), (c) cardiac vagal drive is masked to a lesser extent in chronic hypoxia because of attenuated SNA and lower HR_peak values, and (d) the lower blood lactate levels at altitude is a function of muscle mass involvement rather than adrenergic activation, as normal peak values were reached during exercise with a small muscle mass.     

The acute effects of insulin on the cardiorespiratory responses to hypoxia in streptozotocin‐induced diabetic rats

Aims: We examined whether or not streptozotocin (STZ)‐induced diabetic rats, which have a lower heart rate (HR, beats min^?1) than control rats, could maintain hypoxic ventilatory response. Methods: Twenty‐six Wistar rats, which had been injected with STZ (60 mg kg^?1, EXP) or vehicle (0.1 m citrate buffer, CONT) intraperitoneally at 9 weeks of age, had their cardiorespiratory responses to normoxia and 12%O₂ examined after 5 weeks. Results: Compared with CONT rats, EXP rats had a higher blood glucose [24 ± 3 vs. 5 ± 1 (mean ± SD) mmol L^?1], a lower body weight (320 ± 23 vs. 432 ± 24 g), lower HR (303 ± 49 vs. 380 ± 44 in normoxia, and 343 ± 56 vs. 443 ± 60 in hypoxia) and a lower mean arterial blood pressure (MAP) (89 ± 6 vs. 102 ± 10 mmHg in hypoxia). In contrast, both groups had similar values in ventilation (), –metabolic rate (MR) ratio and arterial blood gases (ABGs). In EXP rats, with an acute insulin supplement (i.v., 0.75 U h^?1 for 1.5–2 h), not only blood glucose, but also HR, and MAP were normalized as those obtained in CONT rats, and in hypoxia further increased without affecting –MR ratio and ABGs. Such acute cardiorespiratory stimulating effects of insulin could not be obtained in non‐diabetic rats (n = 7, 355 ± 24 g), in which euglycaemia (mean 6.4 mmol L^?1) was maintained during the measurements. Conclusions: Our results suggest that, in STZ‐induced diabetic rats: (1) ventilation is hardly suppressed by hyperglycaemia, (2) cardiorespiratory responses can be acutely stimulated by short insulin injection, and (3) the effects, including those through acute blood glucose normalization, are possibly specific for the diabetic impairments.     

高原低氧大鼠肺组织超微结构及其低氧诱导因子1α的表达

背景：低氧诱导因子1α可介导哺乳动物细胞适应低氧环境。 目的：观察高原低氧对大鼠肺组织超微结构的影响及其低氧诱导因子1α表达变化。 方法：将SD大鼠分别为进行高原低氧干预1,2,3和30 d,并设置对照组。4个高原低氧组由海拔5 m的西安地区途中耗时1 d带到海拔2 700 m的青海格尔木地区、途中耗时2 d带到海拔5 000 m的唐古拉地区,途中耗时3,30 d分别带到海拔4 500 m的西藏那曲地区。 结果与结论：光镜及电镜观察显示,急性高原低氧2 d组肺组织出现明显的高原肺水肿,急性高原低氧30 d组低氧诱导因子1α mRNA的表达明显增高(P < 0.01),高原肺水肿现象则明显减轻。结果证实,低氧习服后肺组织低氧诱导因子1α mRNA表达的提高有利于减轻高原肺水肿。     

Acute mountain sickness and physiological stress during intermittent exposure to high altitude

The effect of intermittent exposure to high altitude (4200 m) hypoxia on symptomatology of acute mountain sickness (AMS) was observed, and the relationship between AMS and stress hormone excretion was examined among shift workers at the United Kingdom Infrared Telescope (UKIRT) facility and a control group of sea level residents. Some of the shift workers experienced AMS during their first day at altitude, but had recovered after 5 days residence at altitude. Upon acute exposure to altitude, none of the shift workers reported severe cases of AMS after 5 days residence at sea level, but some reported severe cases after 45 residence at sea level, thus providing some evidence for a 'carry over' of acclimatization for a 5 day period. Reported symptomatology at sea level was predictive of 24 h. excretion rates of adrenaline and 17-hydroxycorticosteroids at high altitude. No good predictors of symptomatology of AMS at high altitude were found using sea level measures alone.     

Contribution of pH,diprotonated phosphate and potassium for the reflex increase in blood pressure during handgrip

The relative importance of pH, diprotonated phosphate (H₂PO₄^?) and potassium (K⁺) for the reflex increase in mean arterial pressure (MAP) during exercise was evaluated in seven subjects during rhythmic handgrip at 15 and 30% maximal voluntary contraction (MVC), followed by post-exercise muscle ischaemia (PEMI). During 15% MVC, MAP rose from 92 ± 1 to 103 ± 2 mmHg, [K⁺] from 4.1 ± 0.1 to 5.1 ± 0.1 mmol L^?1, while the intracellular (7.00 ± 0.01 to 6.80 ± 0.06) and venous pH fell (7.39 ± 0.01 to 7.30 ± 0.01) (P < 0.05). The intracellular [H₂PO₄^?] increased 8.4 ± 2 mmol kg^?1 and the venous [H₂PO₄^?] from 0.14 ± 0.01 to 0.16 ± 0.01 mmol L^?1 (P < 0.05). During PEMI, MAP remained elevated along with the intracellular [H₂PO₄^?] as well as a low intracellular and venous pH. However, venous [K⁺] and [H₂PO₄^?] returned to the level at rest. During 30% MVC handgrip, MAP rose to 130 ± 3 mmHg, [K⁺] to 5.8 ± 0.2 mmol L^?1, the intracellular and extracellular [H₂PO₄^?] by 20 ± 5 mmol kg^?1 and to 0.20 ± 0.02 mmol L^?1, respectively, while the intracellular (6.33 ± 0.06) and venous pH fell (7.23 ± 0.02) (P < 0.05). During post-exercise muscle ischaemia all variables remained close to the exercise levels. Analysis of each variable as a predictor of blood pressure indicated that only the intracellular pH and diprotonated phosphate were linked to the reflex elevation of blood pressure during handgrip.     

Exercise limb blood flow response to acute and chronic hypoxia in Danish lowlanders and Aymara natives

Aim: The femoral artery blood flow response to submaximal, one‐legged, dynamic, knee‐extensor exercise was determined in acute and chronic hypoxia to investigate the hypotheses that with adaptation to chronic hypoxia blood haemoglobin increases, allowing preservation of blood flow as in normoxia. Methods: Sixteen Danish lowlanders participated, in groups of six to eight, in the experiments at sea level normoxia (FiO₂ ? 0.21) and acute hypoxia (FiO₂ ? 0.11), and chronic hypoxia after ～7 and 9–10 weeks at ～5260 m altitude breathing ambient air (FiO₂ ? 0.21) or a hyperoxic gas (FiO₂ ? 0.55). The response was compared with that in six Aymara natives. Results: The haemoglobin and haematocrit increased (P < 0.003) in the lowlanders at altitude vs. at sea level by ～39 and 27% respectively; i.e. to a similar (P = ns) level as in the natives. At rest, blood flow was the same (P = ns) in the lowlanders at sea level and altitude, as in the natives at altitude. During the onset of and incremental exercise, blood flow was the same (P = ns) in the lowlanders at sea level and altitude, as in the natives at altitude. Acute hypoxia increased (P < 0.05) blood flow by ～55% during exercise in the lowlanders at sea level. Acute hyperoxia decreased (P < 0.05) blood flow by ～22–29% during exercise in the lowlanders and natives at altitude. Conclusion: In chronic hypoxia, blood haemoglobin increases, allowing normalization of the elevated exercise blood flow response in acute hypoxia, and preservation of the kinetics and steady‐state exercise blood flow as in normoxia, being similar as in the natives at altitude.     

Limiting factors for exercise at extreme altitudes

Man can only survive and do work in the severe oxygen deprivation of great altitudes by an enormous increase in ventilation which has the advantage of defending the alveolar PO2 against the reduced inspired PO2. Nevertheless the arterial PO2 on the summit of Mt Everest at rest is less than 30 Torr, and it decreases with exercise because of diffusion limitation within the lung. One of the consequences of the hyperventilation is that the marked respiratory alkalosis increases the oxygen affinity of the haemoglobin and assists in loading of oxygen by the pulmonary capillary. Although ventilation is greatly increased, it is a paradox that cardiac output for a given work level is the same in acclimatized subjects at high altitude as at sea level. Stroke volume is reduced but not because of impaired myocardial contractility because this is preserved up to extreme altitudes. Indeed the normal myocardium is one of the few tissues whose function is unimpaired by the very severe hypoxia. There is evidence that oxygen delivery to exercising muscle is diffusion limited along the pathway between the peripheral capillary and the mitochondria. At the altitude of Mt Everest, maximal oxygen uptake is reduced to 20-25% of its sea level value, and it is exquisitely sensitive to barometric pressure. Seasonal variations of barometric pressure affect the ability of man to reach the summit without supplementary oxygen. In spite of the greatly reduced aerobic capacity, anaerobiosis is greatly curtailed, and it is predicted that above 7500 m, there is no rise in blood lactate on exercise. The paradoxically low lactate is possibly related to plasma bicarbonate depletion.     

Hemodynamic responses to hypoxia and hyperoxia in calves at sea level and altitude

Summary Hemodynamic studies were done in nine male Holstein calves, born at sea level, at 250 m (P _B 740 mm Hg) and in eight of these calves after 2 and 4 weeks at 3400 m altitude (P _B 510 mm Hg). Cardiac index (CI) decreased significantly as compared to sea level after 2 weeks at altitude and it was further decreased after 4 weeks. This reduction in CI resulted from decreased stroke index (SI) with unchanged heart rate (HR). Mean pulmonary arterial pressure (PAM) rose from 26 mm Hg at sea level to 63 and 74 mm Hg after 2 and 4 weeks at 3400 m, respectively. Both pulmonary arterial systolic and diastolic pressures were substantially increased at altitude, the diastolic relatively more than the systolic pressure (4.5 fold increase vs. 2.5 fold). Aortic blood pressures (systolic, diastolic and mean) did not change significantly at 3400 m. Right ventricular (systolic) and atrial (mean) pressures increased at altitude.During acute severe hypoxia (P _{IO 2} 55 mm Hg) at sea level CI remained essentially unchanged, while SI and HR, respectively, decreased and rose significantly; PAM was double the normoxic value. Acute hypoxia after 4 weeks at 3400 m did not elicit significant changes in blood gases and pH, CI, SI and HR while PAM increased by 25 mm Hg. There were slight reductions in CI, SI, HR and PAM during acute hyperoxia at sea level. Hyperoxia after 4 weeks at altitude did not change CI, while SI rose significantly; PAM decreased by 30 mm Hg. Apparently, the Holstein calf has a highly reactive pulmonary vascular bed to acute and chronic hypoxia which could make this cattle breed more susceptible to right heart failure during exposure to chronic hypoxia at high altitude.     

Hypoxemia increases serum interleukin-6 in humans

 Serum concentrations of interleukin (IL) 1 beta, IL-1 receptor antagonist (IL-1ra), IL-6, tumor necrosis factor (TNF) alpha, and C-reactive protein (CRP) were determined in ten healthy men at sea level and during four days of altitude hypoxia (4350m above sea level). The mean (SD) arterial blood oxygen saturations were 78.6 (7.3)%, 82.4 (4.9)%, and 83.4 (5.3)% in the first, second, and third days at altitude, respectively. A symptom score of acute mountain sickness (AMS) revealed that the subjects had mostly light symptoms of AMS. Mean serum IL-6 increased from 1.36 (1.04) pg × ml^–1 at sea level to 3.10 (1.65), 4.71 (2.81), and 3,54 (2.17) pg × ml^–1 during the first three days at altitude, and to 9.96 (8.90) pg × ml^–1 on the fourth day at altitude (ANOVA p =0.002). No changes occurred in serum concentrations of IL-1 beta, IL-1ra, TNF alpha, or CRP. The serum IL-6 were related to SaO₂, ( r =–0.45, p =0.003), but not to heart rates or AMS scores. In conclusion, human serum concentrations of IL-6 increased during altitude hypoxia whereas the other proinflammatory cytokines remained unchanged. The major role of IL-6 during altitude hypoxia seem not to be mediation of inflammation, instead, the role of IL-6 could be to stimulate the erythropoiesis at altitude. Accepted: 30 May 1997