Exercise reduces airway sodium ion reabsorption in cystic fibrosis but not in exercise asthma.

When ventilating large volumes of air during exercise, airway fluid secretion is essential for airway function. Since these are impaired in cystic fibrosis and exercise-induced asthma, it was the aim of this study to determine how exercise affects airway Na(+) and Cl(-) transport and whether changes depend on exercise intensity. Nasal potential was measured in Ringer's solution, with amiloride to block Na(+) transport, and in low chloride-containing isoproterenol to assess Cl(-) channels. Nasal potential was measured at rest and during submaximal and maximal bicycle ergometer exercise in individuals with cystic fibrosis, exercise-induced asthma and controls. At rest, nasal potential was significantly higher in cystic fibroses than in the others. Maximal exercise decreased nasal potentials in cystic fibrosis and controls but not in exercise asthma. Submaximal exercise decreased nasal potentials only in cystic fibrosis. Cl(-) transport was not affected. Our results indicate that nasal potentials and Na(+) transport were decreased by maximal exercise in healthy and cystic fibrosis, whereas submaximal exercise decreased potentials in cystic fibrosis only. Exercise did not affect nasal potentials in asthmatics. Decreased reabsorption during exercise might favour airway fluid secretion during hyperpnoea. This protective effect appears blunted in patients with exercise-induced asthma.

No evidence for interstitial lung oedema by extensive pulmonary function testing at 4,559 m.

The aim of the present study was to better understand previously reported changes in lung function at high altitude. Comprehensive pulmonary function testing utilising body plethysmography and assessment of changes in closing volume were carried out at sea level and repeatedly over 2 days at high altitude (4,559 m) in 34 mountaineers. In subjects without high-altitude pulmonary oedema (HAPE), there was no significant difference in total lung capacity, forced vital capacity, closing volume and lung compliance between low and high altitude, whereas lung diffusing capacity for carbon monoxide increased at high altitude. Bronchoconstriction at high altitude could be excluded as the cause of changes in closing volume because there was no difference in airway resistance and bronchodilator responsiveness to salbutamol. There were no significant differences in these parameters between mountaineers with and without acute mountain sickness. Mild alveolar oedema on radiographs in HAPE was associated only with minor decreases in forced vital capacity, diffusing capacity and lung compliance and minor increases in closing volume. Comprehensive lung function testing provided no evidence of interstitial pulmonary oedema in mountaineers without HAPE during the first 2 days at 4,559 m. Data obtained in mountaineers with early mild HAPE suggest that these methods may not be sensitive enough for the detection of interstitial pulmonary fluid accumulation.

Evidence supportive of impaired myocardial blood flow reserve at high altitude in subjects developing high-altitude pulmonary edema.

An exaggerated increase in pulmonary arterial pressure is the hallmark of high-altitude pulmonary edema (HAPE) and is associated with endothelial dysfunction of the pulmonary vasculature. Whether the myocardial circulation is affected as well is not known. The aim of this study was, therefore, to investigate whether myocardial blood flow reserve (MBFr) is altered in mountaineers developing HAPE. Healthy mountaineers taking part in a trial of prophylactic treatment of HAPE were examined at low (490 m) and high altitude (4,559 m). MBFr was derived from low mechanical index contrast echocardiography, performed at rest and during submaximal exercise. Among 24 subjects evaluated for MBFr, 9 were HAPE-susceptible individuals on prophylactic treatment with dexamethasone or tadalafil, 6 were HAPE-susceptible individuals on placebo, and 9 persons without HAPE susceptibility served as controls. At low altitude, MBFr did not differ between groups. At high altitude, MBFr increased significantly in HAPE-susceptible individuals on treatment (from 2.2 +/- 0.8 at low to 2.9 +/- 1.0 at high altitude, P = 0.04) and in control persons (from 1.9 +/- 0.8 to 2.8 +/- 1.0, P = 0.02), but not in HAPE-susceptible individuals on placebo (2.5 +/- 0.3 and 2.0 +/- 1.3 at low and high altitude, respectively, P > 0.1). The response to high altitude was significantly different between the two groups (P = 0.01). There was a significant inverse relation between the increase in the pressure gradient across the tricuspid valve and the change in myocardial blood flow reserve. HAPE-susceptible individuals not taking prophylactic treatment exhibit a reduced MBFr compared with either treated HAPE-susceptible individuals or healthy controls at high altitude.

Hypoxia causes permeability oedema in the constant-pressure perfused rat lung.

Alveolar hypoxia causes pulmonary oedema associated with increased lung capillary pressure and decreased alveolar fluid reabsorption. However, the role of altered permeability is unclear. The aim of the present study was to test whether hypoxia affects alveolar permeability and induces pulmonary oedema in rat lungs, and whether terbutaline affects oedema formation. Isolated lungs of normoxic rats were perfused at a constant pressure (12 cmH2O) and exposed to different levels of oxygenation (1.5-35% O2). Terbutaline (10-5 M) was applied as an aerosol or with the perfusate. Online measurements indicate an earlier onset of weight gain with an increasing degree of hypoxia and a shortened lung survival time (35% O2: approximately 220 min; 1.5% O2: approximately 120 min). Terbutaline did not prevent oedema formation in hypoxic lungs. The terbutaline-induced formation of cyclic adenosine monophosphate was decreased by 50% in hypoxia (1.5% O2). In experiments terminated after 75 min, bronchoalveolar lavage fluid of hypoxic lungs contained protein that originated from perfusate indicating alveolar leakage. Since lactate dehydrogenase in perfusate was not increased at the onset of oedema formation, cell damage does not explain the increased permeability. In conclusion, these results indicate the formation of a leak for macromolecules of the isolated perfused rat lung, which is accelerated by hypoxia and causes alveolar flooding even at low perfusion pressure at a rate that exceeds absorption even after stimulation with terbutaline.

Platelet count and function at high altitude and in high-altitude pulmonary edema.

Platelet aggregation is the key process in primary hemostasis. Certain conditions such as hypoxia may induce platelet aggregation and lead to platelet sequestration primarily in the pulmonary microcirculation. We investigated the influence of high-altitude exposure on platelet function as part of a larger study on 30 subjects with a history of high-altitude pulmonary edema (HAPE) and 10 healthy controls. All participants were studied in the evening and the next morning at low altitude (450 m) and after an ascent to high altitude (4,559 m). Platelet count, platelet aggregation (platelet function analyzer PFA100; using epinephrine and ADP as activators), plasma soluble P (sP)-selectin, and the coagulation parameters prothrombin fragments 1+2 and thrombin-antithrombin complex were measured. High-altitude exposure decreased the platelet count, shortened the platelet function analyzer closure time by approximately 20%, indicating increased platelet aggregation, increased sP-selectin levels to approximately 250%, but left plasma coagulation unaffected. The HAPE-susceptible subjects were prophylactically treated with either tadalafil (a phosphodiesterase 5 inhibitor), dexamethasone, or placebo in a double-blind way. Subgroup analyses between these different treatments and comparisons of the seven placebo-treated individuals developing HAPE and controls revealed no differences in platelet count, platelet aggregation, or sP-selectin values. We conclude that exposure to high altitude activates platelets, which leads to platelet aggregation, platelet consumption, and decreased platelet count. These effects are, however, not more pronounced in individuals with a history of HAPE or actually suffering from HAPE than in controls and therefore may not be a pathophysiological mechanism of HAPE.

[Acute mountain sickness and high-altitude pulmonary edema. How to protect the mountain climber from the effects of the "altitude haze"]. / Akute Bergkrankheit und Höhenlungenödem. Wie Sie Bergsteiger vor den Folgen des "Höhenrauschs" bewahren.

Acute mountain sickness (AMS) usually occurs after 6-12 hours of acute exposure to altitudes above 2,500 m. If there is no further altitude gain, it normally resolves spontaneously within a day or two. However, it may, in rare cases, progress to life-threatening cerebral edema. High-altitude pulmonary edema (HAPE) is a non-cardiogenic edema that is often preceded by symptoms of AMS. The major preventive measure is slow ascent. Acetazolamide and dexamethasone are effective in preventing AMS, while nifedipine is effective only against HAPE. Immediate descent and/or the administration of oxygen is the treatment of choice for both conditions. If this is not possible, dexamethasone may be given for severe AMS and nifedipine for HAPE.

Hypoxia-effects on Ca(i)-signaling and ion transport activity of lung alveolar epithelial cells.

In excitatory cells specific responses upon changes in PO(2) are mediated by changes in intracellular Ca (Ca(i)). We wanted to know whether ion transport of lung alveolar epithelial cells is regulated by Ca(i) and whether Ca(i) and Ca(i) -signaling are affected by hypoxia in a way that might explain hypoxic transport inhibition (Mairbäurl et al. AJP 273: L797, 1997). The activity of transport (Na/K-pump, Na/K/2Cl-cotransport) was measured as unidirectional (86)Rb-uptake after A549 cells were exposed to hypoxia (3% O(2)). Ca(i) of primary cultured rat alveolar type II cells was measured by fura-2 epifluorescence. Depletion of Ca(i) by extracellular chelators in presence of ionomycin or with thapsigargin as well as PKC inhibition decreases (86)Rb-uptake of normoxic and hypoxic A549 cells, whereas an increased Ca(i) activates transport. Neither immediate nor prolonged exposure to hypoxia changes Ca(i) significantly. The increase in Ca(i) upon stimulation with ATP, which is caused mainly by release from intracellular stores, is smaller in hypoxia than in normoxia. These results indicate that ion transport of alveolar epithelial cells is modulated by Ca(i). A change in Ca(i) does not mediate hypoxic transport inhibition. The decreased Ca(i) transients in hypoxia might indicate a blunted response to extracellular stimuli.

Effects of iron repletion on blood volume and performance capacity in young athletes.

PURPOSE: The purpose of this study was to find out whether iron repletion leads to an increase in red blood cell volume (RBV) and performance capacity in iron-deficient nonanemic athletes. METHODS: 40 young elite athletes (13-25 yr) with low serum ferritin (< 20 microg.L-1) and normal hemoglobin (males > 13.5 g.dL-1, females > 11.7 g.dL-1) were randomly assigned to 12-wk treatment with either twice a day ferrous iron (equivalent to 2 x 100 mg elemental iron) or with placebo using a double blind method. Before and after treatment, hematological measures and parameters of iron status were determined in venous blood. RBV, blood volume (BV), and plasma volume (PV) were measured by CO rebreathing. For determination of the aerobic and anaerobic capacity (maximal accumulated oxygen deficit, MAOD), the athletes performed an incremental as well as a highly intensive treadmill test. RESULTS: After 12 wk, ferritin levels were within the normal range in the iron-treated group (IG) with a significant (P < 0.001) mean increase by 20 microg.L-1 opposed to a slight nonsignificant decrease in the placebo group (PG). RBV did not change significantly in either group nor did any of the hematological measures. However, only in IG there were significant increases in VO2max and in O2 consumption in the MAOD test. MAOD and maximal capillary lactate concentration remained unchanged in both treatment groups. CONCLUSIONS: The results indicate that in young elite athletes with low serum ferritin and normal hemoglobin concentration iron supplementation leads to an increase in maximal aerobic performance capacity without an augmentation of RBV.

Hypoxia decreases proteins involved in epithelial electrolyte transport in A549 cells and rat lung.

Fluid reabsorption from alveolar space is driven by active Na reabsorption via epithelial Na channels (ENaCs) and Na-K-ATPase. Both are inhibited by hypoxia. Here we tested whether hypoxia decreases Na transport by decreasing the number of copies of transporters in alveolar epithelial cells and in lungs of hypoxic rats. Membrane fractions were prepared from A549 cells exposed to hypoxia (3% O(2)) as well as from whole lung tissue and alveolar type II cells from rats exposed to hypoxia. Transport proteins were measured by Western blot analysis. In A549 cells, alpha(1)- and beta(1)-Na-K-ATPase, Na/K/2Cl cotransport, and ENaC proteins decreased during hypoxia. In whole lung tissue, alpha(1)-Na-K-ATPase and Na/K/2Cl cotransport decreased. alpha- and beta-ENaC mRNAs also decreased in hypoxic lungs. Similar results were seen in alveolar type II cells from hypoxic rats. These results indicate a slow decrease in the amount of Na-transporting proteins in alveolar epithelial cells during exposure to hypoxia that also occurs in vivo in lungs from hypoxic animals. The reduced number of transporters might account for the decreased transport activity and impaired edema clearance in hypoxic lungs.

Cation transport and cell volume changes in maturing rat reticulocytes.

During maturation, reticulocytes lose membrane material, including transporters, and this is accompanied by a loss of cell water and volume. Here we determined a possible role of ion transport in adjusting cell volume during maturation. Reticulocytes and red blood cells of different ages were prepared from erythropoietin-treated rats by density gradient fractionation. Cell volume and ion transport were measured in freshly prepared cells and in reticulocytes during in vitro maturation. Reticulocytes had an increased K content and cell volume, whereas intracellular Na was decreased. All parameters approached whole blood values after 2 days in culture. Na-K pump was elevated in reticulocytes and decreased during maturation. Na-K-2Cl cotransport (NKCC) activity was lower in reticulocytes and was activated 8- and 20-fold by shrinkage and okadaic acid, respectively, whereas stimulation was barely detectable in high-buoyant density red blood cells. The ouabain- and bumetanide-insensitive Na flux in reticulocytes decreased on maturation. Most of it was inhibited by amiloride, indicating the presence of Na/proton exchange. Our results show that, although the Na-K-pump activity in reticulocytes is very much increased, the enhanced capacity of NKCC is essentially cryptic until stimulated. Both types of capacities (activities) decrease during maturation, indicating a possible loss of transport protein. The decrease was constrained to the period of reticulocyte maturation. Loss of transport capacity appears to exceed the loss of membrane surface area. Reticulocyte age-related changes in the net electrochemical driving force indicate that the increasing NKCC activity might contribute to the reduction in cell water.

Possible role of ROS as mediators of hypoxia-induced ion transport inhibition of alveolar epithelial cells.

In oxygen-sensitive excitable cells, responses to hypoxia are initiated by membrane depolarization due to closing of the K channels that is thought to be mediated by a decrease in reactive oxygen species (ROS). Because the mechanisms of hypoxic inhibition of ion transport of alveolar epithelial cells (Planes C, Friedlander G, Loiseau A, Amiel C, and Clerici C. Am J Physiol Lung Cell Mol Physiol 271: L70-L78, 1996; Mairbäurl H, Wodopia R, Eckes S, Schulz S, and Bärtsch P. Am J Physiol Lung Cell Mol Physiol 273: L797-L806, 1997) are not yet understood, we tested the possible involvement of a hypoxia-induced change in ROS that might control transport activity. Transport was measured as (86)Rb and (22)Na uptake in A549 cells exposed to normoxia, hyperoxia, or hypoxia together with ROS donors and scavengers. H(2)O(2) < 1 mM did not affect transport, whereas 1 mM H(2)O(2) activated (22)Na uptake (+200%) but inhibited (86)Rb uptake (-30%). Also hyperoxia, aminotriazole plus menadione, and diethyldithiocarbamate inhibited (86)Rb uptake. N-acetyl-L-cysteine, diphenyleneiodonium, and tetramethylpiperidine-N-oxyl, used to reduce ROS, inhibited (86)Rb uptake, thus mimicking the hypoxic effects, whereas deferoxamine, superoxide dismutase, and catalase were ineffective. Also, hypoxic effects on ion transport were not prevented in the presence of H(2)O(2), diethyldithiocarbamate, and N-acetyl-L-cysteine. These results indicate that ion transport of A549 cells is significantly affected by decreasing or increasing cellular ROS levels and that it is possible that certain species of ROS might mediate the hypoxic effects on ion transport of alveolar epithelial cells.

Effects of iron supplementation on total body hemoglobin during endurance training at moderate altitude.

The aim of the study was to test the hypothesis that iron supplementation in well-trained non-iron-depleted athletes leads to an enhanced increase of total body hemoglobin (TBH) during training at moderate altitude. Therefore, the members of the national German boxing team were randomly assigned to treatment with ferrous-glycine-sulfate (1335 mg equivalent to 200mg elementary iron daily) or with placebo during 18 days of endurance training at moderate altitude (1800 m). Before and after altitude training TBH was determined by CO-rebreathing, measures of exercise performance were determined with an incremental treadmill test. Before, during and after the stay at moderate altitude erythropoietin (Epo), reticulocytes (Retics) and parameters of iron metabolism were measured in venous blood. The results show that TBH did not change significantly in the placebo-group and even slightly, but significantly decreased in the iron-treated group. However, there was a significant increase of Epo and Retics in both groups during training at moderate altitude whereas parameters of iron metabolism remained unchanged. VO2max did not change either. To test whether a training-induced hemolysis, an increased urinary iron excretion or gastrointestinal blood loss could explain the unexpected drop of TBH we tested most of the boxers again during a similar training camp at low altitude (400-1000 m) to obtain measures of hemolysis, urinary iron excretion and occult hemoglobin loss with the stools. Although there were signs of an increased erythrocyte turnover no iron loss could be observed. We conclude that 18 days of endurance training at an altitude of 1800 m does not lead to an increase of TBH in non-iron-depleted athletes with and without iron supplementation.

Lack of effect of oral Mg-supplementation on Mg in serum, blood cells, and calf muscle.

UNLABELLED: Magnesium (Mg) is important for regulating ion transport and cellular metabolism in all body tissues. In skeletal muscle Mg is involved in the neuromuscular activity, excitation, and muscle contraction. Mg deficiency can cause muscle weakness and muscle cramps. Less than 1% of total body Mg is found in serum, yet the serum Mg concentration is used to assess the body's Mg status. PURPOSE: The purpose of this study was to determine whether an oral Mg supplementation (500 mg Mg-oxide.d-1 for 3 wk) affects exercise performance, clinical symptoms, and the Mg concentration in various body compartments in athletes with low-normal serum Mg levels (N = 10 in each group). METHODS: In a double-blind, placebo-controlled study, correlation analysis between the Mg concentration in serum, blood cells, and skeletal muscle was performed to establish a measure for muscle cell Mg. RESULTS: The data indicate that a 3-wk Mg supplementation did not affect exercise performance, neuromuscular activity, or muscle related symptoms. Also, the supplementation did not increase the Mg concentration in serum or any cellular compartment studied. However, in the placebo group the renal Mg clearance decreased, whereas it increased in the subjects receiving Mg supplementation. Correlation analysis revealed that serum Mg only correlated with red cell Mg and that only leukocyte Mg correlated with the nuclear magnetic resonance (NMR)-measured muscle cell Mg concentration. CONCLUSIONS: These results indicate that Mg supplementation in athletes with low-normal serum Mg did not improve performance and failed to increase the body's Mg stores. Serum Mg appears to be a poor indicator for Mg in skeletal muscle or most other cellular compartments, but the concentration of Mg in mononuclear leukocytes might be used as an indicator of skeletal muscle Mg when NMR is not available.

Red blood cells do not contribute to removal of K+ released from exhaustively working forearm muscle.

K+ released from exercising muscle via K+ channels needs to be removed from the interstitium into the blood to maintain high muscle cell membrane potential and allow normal muscle contractility. Uptake by red blood cells has been discussed as one mechanism that would also serve to regulate red blood cell volume, which was found to be constant despite increased plasma osmolality and K+ concentration ([K+pl]). We evaluated exercise-related changes in [K+pl], pH, osmolality, mean cellular Hb concentration, cell water, and red blood cell K+ concentration during exhaustive handgrip exercise. Unidirectional 86Rb+ (K+) uptake by red blood cells was measured in media with elevated extracellular K+, osmolarity, and catecholamines to simulate particularly those exercise-related changes in plasma composition that are known to stimulate K+ uptake. During exercise [K+pl] increased from 4.4 +/- 0.7 to 7.1 +/- 0.5 mmol/l plasma water and red blood cell K+ concentration increased from 137.2 +/- 6.0 to 144.6 +/- 4.6 mmol/l cell water (P

[Pseudo-anemia caused by sports]. / Pseudoanämie durch Sport.

Regular physical training leads to an increase of plasma volume by 10-20 percent. Therefore, hemoglobin concentration slightly below normal values in the presence of low-normal serum ferritin levels in athletes are usually due to a dilutional "pseudoanemia". Several cross sectional studies indicate that true iron deficiency anemia is not more frequent in athletes than in the general population. Since regular physical activity, especially extensive, running increases iron loss, mild iron deficiency (abnormal serum ferritin and normal hemoglobin concentration) and sometimes true iron deficiency anemia can occur especially when nutritional iron intake is insufficient and iron demand is increased because of growth (children, adolescents) or additional iron loss (menstruation). Several controlled studies indicate that iron supplementation (recommended dose 2 x 100 mg elementary iron/day) improves performance only when hemoglobin concentration increases, i.e. when iron deficiency anemia is present. On the contrary, iron supplementation has no measurable effects on performance when hemoglobin concentration cannot be increased, i.e. in mild iron deficiency.

Impairment of cation transport in A549 cells and rat alveolar epithelial cells by hypoxia.

A reduced cation reabsorption across the alveolar epithelium decreases water reabsorption from the alveoli and could diminish clearing accumulated fluid. To test whether hypoxia restricts cation transport in alveolar epithelial cells, cation uptake was measured in rat lung alveolar type II pneumocytes (AII cells) in primary culture and in A549 cells exposed to normoxia and hypoxia. In AII and A549 cells, hypoxia caused a PO2-dependent inhibition of the Na-K pump, of Na-K-2Cl cotransport, and of total and amiloride-sensitive 22Na uptake. Nifedipine failed to prevent hypoxia-induced transport inhibition in both cell types. In A549 cells, the inhibition of the Na-K pump and Na-K-2Cl cotransport occurred within approximately 30 min of hypoxia, was stable >20 h, and was reversed by 2 h of reoxygenation. There was also a reduction in cell membrane-associated Na-K-ATPase and a decrease in Na-K-2Cl cotransport flux after full activation with calyculin A, indicating a decreased transport capacity. [14C]serine incorporation into cell proteins was reduced in hypoxic A549 cells, but inhibition of protein synthesis with cycloheximide did not reduce ion transport. In AII and A549 cells, ATP levels decreased slightly, and ADP and the ATP-to-ADP ratio were unchanged after 4 h of hypoxia. In A549 cells, lactate, intracellular Na, and intracellular K were unchanged. These results indicate that hypoxia inhibits apical Na entry pathways and the basolateral Na-K pump in A549 cells and rat AII pneumocytes in culture, indicating a hypoxia-induced reduction of transepithelial Na transport and water reabsorption by alveolar epithelium. If similar changes occur in vivo, the impaired cation transport across alveolar epithelial cells might contribute to the formation of hypoxic pulmonary edema.

Na(+)-K(+)-2Cl- cotransport, Na+/H+ exchange, and cell volume in ferret erythrocytes.

Ferrets have high-Na+ and low-K+ erythrocytes (113 and 5.4 mmol/l cell water) due to the lack of Na(+)-K+ pumps. Because ferret erythrocytes have a high capacity for Na(+)-K(+)-2Cl- cotransport, the present study was undertaken to evaluate cell volume-related changes in cotransport activity and its role in volume regulation. With cell shrinkage, Na(+)-K(+)-2Cl- cotransport is activated about twofold. A large bumetanide-insensitive Na+ uptake component that has not yet been described is found in shrunken erythrocytes. Its inhibition by amiloride (concn inhibiting 50% of maximal response = 12 microM) and the Na+ dependence of amiloride-sensitive extracellular pH changes measured in cells suspended in hypertonic unbuffered medium indicate that this flux represents Na+/H+ exchange. Shrinkage activation of both transporters follows a time lag of approximately 3 min and also requires normal levels of ATP. ATP depletion inhibits Na(+)-K(+)-2Cl- cotransport even at normal cell volume. Both transporters are partially inhibited by the protein kinase inhibitors staurosporine and K252a, and activators of protein kinases A and C do not affect transport. Okadaic acid inhibition of protein phosphatases activates Na(+)-K(+)-2Cl- cotransport to its maximal activity (same after shrinkage), but shrinkage and okadaic acid activation are not additive. In contrast, okadaic acid activates Na+/H+ exchange even in shrunken cells. These results indicate that cell shrinkage activates Na(+)-K(+)-2Cl- cotransport and Na+/H+ exchange probably by phosphorylation processes.

Red blood cell function in hypoxia at altitude and exercise.

Oxygen transport by red blood cells is regulated by erythropoiesis and Hb-O2-affinity. The O2 carrying capacity is characterized by changes in hematocrit, red blood count or the mass of circulating red blood cells. Erythropoiesis is controlled by the hormone erythropoietin, which induces slow changes of the O2-transport capacity. The Hb-O2-affinity is modified mainly by pH and 2,3-DPG. Despite their apparently diverse effects e.g. in hypoxia at high altitude, a compromise seems to be adopted optimizing both arterial O2-loading and peripheral O2-unloading. In contrast to erythropoiesis, adjustments of the Hb-O2-affinity occur fast and allow rapid adjustments of O2-binding and release. In the intact organism the significance of changes in Hb-O2-affinity for tissue oxygen supply relative to adjustments of cardiac output, microcirculation and O2-transport capacity is not completely understood yet, but beneficial effects were demonstrated in isolated organs. It is, however, the least energy-demanding way of optimizing tissue O2-supply, which might be of significance in extreme situations. In severe hypoxia adjustments of both, hematocrit and Hb-O2-affinity, are insufficient to maintain tissue O2-supply. Alterations of Hb-O2-affinity are also insufficient to compensate for severe anemia.

Interactions between Hb, Mg, DPG, ATP, and Cl determine the change in Hb-O2 affinity at high altitude.

Ascent to high altitude (HA) causes an increase in erythrocyte 2,3-diphsophoglycerate (DPG) and standard PO2 at 50% O2 saturation, PCO2 40 Torr, and blood pH 7.4 (P50,st). We studied the early phase of acclimatization to HA of mountaineers without and with a history of HA pulmonary edema. Tests were performed before ascent and after arrival at HA (4,559 m), approximately 22 h after the departure from low altitude (HA1) and on the following 3 days at HA (HA2-HA4). We investigated the relation between changes in DPG and P50,st, since at moderate altitude P50,st increases more rapidly than DPG, indicating that other factors may contribute to the change in P50,st. Combined effects of interaction between allosteric effectors of hemoglobin (Hb) (DPG, ATP, Cl) and Mg, which competes with Hb for DPG and ATP binding, might explain that phenomenon. Therefore concentrations of liganded Hb species were calculated from the total erythrocyte concentrations of the ligands by use of published binding constants and were related to changes in Hb-O2 affinity. P50,st increased at HA by approximately 4.5 Torr; the concentration of total DPG and ATP increased by 28 and 19%, respectively. Whereas P50,st reached a plateau already at HA1, the concentration of DPG reached its highest value at HA4. The erythrocyte Cl concentration decreased, whereas cellular Hb and Mg concentrations increased slightly. The sum of concentrations of all liganded Hb species increased, reaching 79% of its total change within 22 h after ascent; this can mainly be attributed to the change in the concentration of Hb[DPG] (+77% of total increase).(ABSTRACT TRUNCATED AT 250 WORDS)