The main function of red blood cells is to transport respiratory gases. In the lungs, oxygen (O 2 ) diffuses from the inhaled air across the alveolar barrier into the blood, where most of it combines with hemoglobin (Hb) to form oxygenated Hb, a process called oxygenation. Hb is contained in red blood cells and circulates through the cardiovascular system, transporting O to the periphery where it is released from Hb bonds (deoxygenated) and diffuses into the cell. While passing through peripheral capillaries, carbon dioxide (CO 2 ) produced by cells reaches red blood cells, where carbonic anhydrase (CA) in tissues and red blood cells converts most of the CO 2 into bicarbonate (HCO - 3 ). Carbon monoxide also binds to Hb, preferentially forming carboxyl bonds through deoxygenated Hb. Both forms of CO are transported to the lungs, where CA converts HCO - 3 back to CO . CO2 is also released from its binding to Hb and diffuses across the alveolar walls to be exhaled.
The biological significance of Hb transport of O2 is well illustrated by anemia, in which reduced Hb also reduces exercise performance despite an increase in cardiac output and improves aerobic exercise performance when total Hb is increased. Figure 1, O2 dissociation curve showing the predominance of normal versus anemic Hb, showing that at any given partial pressure of O2 ( PO2 ), the O2 content in the blood changes with the Hb concentration in the blood. Not only its quantity but also the functional properties of Hb affect performance. Increased Hb- O affinity was observed to favor O loading in the lungs and survival in hypoxic environments, while this was illustrated by decreased Hb-O affinity . Affinity favors the release of O from Hb molecules to support oxidative phosphorylation when ATP demand is high, such as during exercise of skeletal muscle.
Despite O2 transport, red blood cells perform a variety of other functions, all of which can also enhance athletic performance. Perhaps the most important one is the role of red blood cells in buffering changes in blood pH, both by transporting CO2 and by binding H+ to hemoglobin. Red blood cells also absorb metabolites such as lactate released from skeletal muscle cells during high-intensity exercise. Ingestion of red blood cells decreases plasma concentrations of metabolites. Finally, erythrocytes appear to be able to reduce peripheral vascular resistance by releasing the vasodilator NO and stimulate endothelial NO formation by releasing ATP, leading to arteriolar vasodilation and increased local blood flow.
hemoglobin oxygen affinity
The primary mechanism for optimizing O2 transport by hemoglobin is changes in Hb-O2 affinity. The changes are very rapid and actually occur as the red blood cells pass through the capillaries. The effect of altered Hb-O2 affinity on O2 transport is independent of circulating Hb concentration and total Hb mass and is therefore modulated by increased changes in erythropoiesis.
Hemoglobin has a very high intrinsic O2 affinity. Therefore, there is a need for allosteric effectors that reduce Hb-O2 affinity, thereby allowing O2 to be unloaded from Hb molecules. The major allosteric effectors that regulate Hb-O affinity in human erythrocytes are organophosphates such as 2,3-bisphosphoglycerate (2,3-DPG) and adenosine triphosphate (ATP), H and CO, and Cl -. The direct effect of lactate accumulated during exercise on Hb-O2-affinity is unclear and may be due to a minimal effect on Cl- binding to Hb and carbamate formation. The indirect effects of lactate may be caused by effects on Cl − concentrations and absorption of H + and lactate mediated by MCT-1. Another modulator of Hb-O affinity associated with exercise is changes in body temperature. Figure 1 shows that acidosis and increases in CO and 2,3-DPG reduce Hb-O affinity at any Hb concentration. Cl - changes very little in vivo and is therefore not shown in the graph. Furthermore, increasing temperature reduces Hb-O affinity. These changes shift the ODC to the right, graphically showing that the O2 saturation of Hb(SO2) decreases at any given PO2. Conversely, alkalosis, CO2, a decrease in 2,3-DPG, and temperature increase the affinity of Hb-O2 to increase SO2 at a given PO2.
The physiological significance of increased Hb-O affinity is that the binding of Hb to O is improved when PO is low. Therefore, it may prevent excessive arterial desaturation in individuals exposed to hypoxic conditions. Reduced Hb-O affinity improves O delivery to cells with high O demand, such as in exercising muscles.
Hb-O affinity during exercise
During exercise, increased oxygen demand can be met by increased muscle blood flow as well as improved O2 unloading from Hb by reducing Hb-O2 affinity. It is clear that if the reduction in Hb-O affinity is systemic—i.e., in all red blood cells in circulation—it will impair arterial O loading of Hb in the lungs. Therefore, it would be advantageous if Hb-O2 affinity was adjusted locally to serve both functions, oxygenation in the lungs and deoxygenation in peripheral blood capillaries. Therefore, Hb-O2 affinity should be lower when red blood cells pass through tissues with high O2 demand, and should increase when red blood cells return to the lungs. This actually occurs due to significant differences in pH, CO2, and temperature between the lungs and capillaries in the working muscles. 2,3-DPG is one of the major allosteric effectors of Hb-O2 affinity and no changes were observed during exercise testing because 2,3-DPG changes slowly and is required to adjust the glycolysis rate in red blood cells. However, 2,3-DPG was found to be elevated after training. It may be considered beneficial for O2 unloading during exercise because it increases the effect of acidosis on Hb-O2 affinity. Elevated 2,3-DPG in trained individuals may be the result of stimulated erythropoiesis, which decreases erythrocyte age. Compared with aged erythrocytes, young erythrocytes have higher metabolic activity, higher 2,3-DPG, and lower Hb-O2 affinity.
O2 is unloaded into exercising muscles. Muscle cells that exercise release H+, CO2, and lactic acid into the capillaries, and the temperature in working muscles is also higher than in inactive tissue. Blood entering the capillaries of the exercising muscles is drastically affected by these changes, which results in a rapid decrease in Hb-O affinity. The P50 value is approximately 34–48 mmHg and can be estimated from changes in blood gases. The temperature increased from 37°C during rest to 41°C during exercise. Because the mixing of metabolites causes constant changes in blood composition as new blood enters the capillaries, the P50 value on the arterial side of the capillary is lower than its venous end, resulting in a huge right shift of ODC within the capillary, thereby significantly increasing O in Hb Unloading of 2. This is also evidenced by the extensive movement of the right side of ODC in capillary blood under exercise conditions relative to rest (Fig. 2; 2; points D and B, respectively). Trained individuals have a higher Bohr effect at low SO2, possibly due to elevated 2,3-DPG, which may result in a greater increase in arteriovenous O2 differences.
Arterial O2 Load On the way from working muscles to the lungs, the concentration of H+ and CO2 in the blood is reduced by the mixture of blood from inactive muscles and other organs. Due to alveolar gas exchange, CO2 is reduced in the alveolar capillaries, further alkalizing the blood. Therefore, the effects of these metabolites on Hb-O affinity are attenuated in the lung relative to working muscle. The temperature of the lungs is also lower than that of the working muscles. However, during strenuous exercise, the normal value of Hb-O affinity was not fully restored, which was manifested by a slight shift of the right side of the ODC under exercise conditions relative to the resting condition (Fig. 2; 2; points A and C). The size of the deviation depends on the amount of active muscle and the intensity of the exercise. Blood gas data during exercise can estimate that the half-saturated tension of O2 (P50 value) may increase from approximately 27 mmHg at rest to 34 mmHg in the arterial blood during strenuous exercise. This reduction in Hb-O affinity impairs arterial O loading and reduces arterial SO from approximately 97.5% at rest to approximately 95% during high-intensity exercise. Increased 2,3-DPG in trained individuals may further reduce arterial SO 2 . In addition to the effect of reduced Hb-O2 affinity, SO2 is further reduced because the shortened contact time when cardiac output is high limits diffusion and may even be enhanced when exercise occurs. Performed under hypoxic conditions.
When comparing the effects of acidic metabolites and increased body temperature during exercise on Hb-O affinity in arterial and muscle capillary blood, it is apparent that the changes in working muscles are much greater than those in the lungs. Therefore, arterial desaturation during exercise is easily compensated by the greatly increased amount of O2 unloaded from Hb relative to rest.
Oxygen delivery capacity
Although only 0.03 ml O2*L-1*mmHg-1 PO2 can be transported in the blood in a physical solution at 37°C, one gram of Hb can bind approximately 1.34 ml O2. Therefore, the presence of normal amounts of Hb per volume of blood increases the amount of transportable O2 by approximately 70-fold, which is absolutely necessary to meet the O2 requirements of normal tissues. It is therefore clear that increasing the amount of Hb also increases the amount of O2 that can be delivered to the tissue (Figure 1). In fact, O transport capacity has been found to be directly related to aerobic performance, as evidenced by improved performance following red blood cell transfusion and a strong correlation between total Hb and maximal O uptake in athletes (VO, max ). Acute manipulation of O2 carrying capacity can also alter performance. Therefore, for aerobic performance, having a high O2 transfer capacity is a clear advantage.
Parameters required to assess O2 transport capacity are Hb concentration (cHb) and hematocrit (Hct) in the blood, as well as total Hb mass (tHb) and total corpuscular volume (tEV) in the circulation. cHb and Hct are easy to measure using standard hematology laboratory equipment. Together with SO2, they represent the amount of O2 that can be delivered to the periphery per unit of cardiac output. tHb and tEV represent the total amount of O2 that can be transported through the blood. Large tHb and tEV allow redirection of O2 to organs with high O2 demand while maintaining basal O2 supply in less active tissues. Because they are affected by changes in plasma volume (PV), cHb and Hct cannot draw conclusions about tHb and tEV, respectively.
cHb, Hct, and red blood cell count results in athletes and their comparison with healthy, sedentary individuals are conflicting because red blood cell volume and PV vary independently and because many factors influence each of these parameters. Determining normal values for tHb and tEV for athletes is further hampered by the possibility of using methods that increase aerobic capacity such as blood and erythropoietin (EPO) stimulants.
Athletes' hematocrit
Many, but not all, studies show that athletes have lower Hct (hematocrit level is the percentage of red blood cells in the blood) than sedentary controls. However, some studies have also reported higher than normal Hct. Highly increased Hct increases blood viscosity and increases the workload of the heart. Therefore, it carries the risk of overloading the heart.
Many studies show that athletes tend to have lower Hct than sedentary people. In the process of establishing reference Hct and Hb values for athletes. The study found that among approximately 1,100 athletes from different countries, 85% of female and 22% of male athletes had Hct values below 44%. Also shown is a trend for Hct to be negatively correlated with training status, represented by VO 2,max. However, a small proportion of sedentary controls and athletes had higher than normal Hct. In the study, 1.2% of women and 32% of men had Hct >47%. When female and male elite athletes and controls were followed over the 43-month study period, 6 male controls and 5 male athletes had Hct >50% and 5 female controls but no female athletes had Hct >47%.
Changes in hematocrit Hct occur rapidly during exercise. When fluid replacement during exercise is insufficient, Hct during exercise increases due to a decrease in PV. As a result of sweating, plasma water is transferred to the extracellular space due to the accumulation of osmotically active metabolites, as well as filtration due to increased capillary hydrostatic pressure. The resulting increase in plasma protein increases osmotic pressure, thereby moderating fluid escape. Changes during swimming appear to be less pronounced than during running, in which case immersion and redistribution of blood volume appear to result in changes in PV independent of volume-regulating hormones. An increase in hematocrit due to catecholamine-induced sequestration of red blood cells in the spleen is unlikely in humans but has been found in other species.
Long-term changes in hematocrit were reported in a recent review of 12 studies in more than 600 healthy, non-smoking, mostly sedentary individuals, over a period of days to 2 months. Data from 18 investigations were summarized and it was found that PV and blood volume increased rapidly after training, while red blood cell volume remained unchanged for several days before starting to increase, indicating that Hct values decreased over several days. The magnitude of Hct changes appears to depend on the intensity and type of exercise during training. A few weeks after the training intervention, a new steady state is established and Hct returns to pretraining values. The increase in PV after training and in highly trained athletes may result from aldosterone-dependent renal Na+ reabsorption, as well as water retention stimulated by elevated antidiuretic hormone to compensate for water loss during individual training.
There appears to be considerable seasonal variation in Hct (relative variation up to 15%), with summer values being lower than winter, which may result in inter-seasonal variation, around 42% in summer and 48% in winter, as seen in thousands of study participants . Seasonal changes depend on climatic influences, with greater differences in countries closer to the equator. Studies of seasonal changes in Hct in athletes are sparse but suggest that Hct may be reduced by an additional 1-2% in the summer through increased training effects.
Total hemoglobin mass (tHb) and total corpuscular volume (tEV)
As mentioned above, PV is prone to acute changes, whereas changes in total red blood cell mass (or volume) are slow due to the slow rate of erythropoiesis. Therefore, in addition to cHb and Hct, total hemoglobin and/or red blood cell volume must be measured to obtain a reliable measure of oxygen transport capacity. Several methods have been applied to determine these parameters.
A person using the carbon monoxide (CO) rebreathing method to measure blood volume. This method is based on the fact that the affinity of Hb for CO is much higher than for O, which allows the use of CO in the indicator dilution method. It has been used to measure the ratio of blood mass relative to body weight. This technique has been greatly improved by improved methods for estimating carboxyhemoglobin. To date, CO rebreathing or inhalation has been further improved. MCHC is then used to calculate tEV, and Hct is used to estimate total blood volume. Total red blood cell volume can be measured directly after injection of 99m Tc-labeled red blood cells. By indirect means, total red blood cell volume can also be calculated from Hct after measuring PV using albumin-bound Evans blue (T-1824) and by injecting 125-iodine-labeled albumin. Several of these methods were compared. reported a correlation of r = 0.99 with 125 measured PV for I-albumin and Evans blue, and showed that the PV calculated from tEV measurements with labeled red blood cells was approximately 5-10% lower than that for labeled albumin.
Applying these techniques et al. Trained individuals were found to have increased tHb, a result that has since been confirmed multiple times by comparing groups of individuals with different training status and by measuring tEV before and after extended training periods. Recently concluded that different training methods have different effects on tHb, and they mainly emphasized hypoxic training. Taken together, these studies show that for a 1 g increase in tHb, for example, by administration of erythropoietin, VO 2,max increases by approximately 3 ml/min. It can be concluded that an increase of 1 g tHb per kilogram of body weight (g/kg) will increase VO 2,max by approximately 5.8 ml/min/kg, while for non-athletes (although VO 2 is quite high), max of 45 ml/min/kg ) had a tHb of 11 g/kg and their best athlete (mean VO 2,max = 71.9 ml/kg) had a tHb of 14.8 g/kg. Their findings are in good agreement with reported results, which found that elite athletes tHb is 37% higher than untrained people. Combining the results of several of their studies, it was found that for every 1 g/kg change in tHb, the change in VO 2,max was 4.2 ml/min/kg in men and 4.4 ml/min/kg in women, a very high correlation coefficient (r ~ 0.79), while there is no correlation between VO 2,max and Hb or Hct. However, a lack of difference in tHb between sedentary and trained individuals has also been reported. As mentioned above, all of these studies bear the uncertainty that athletes may have taken steps to improve performance, making it difficult to determine "normal values" for tHb and tEV for athletes.
Different durations of exercise training (weeks vs. months) appear to explain the different results in tHb and training studies. Soka et al. ( 2000 ) found no increase when training duration was less than 11 days. Furthermore, most studies of 4-12 months of training show no or only small effects; their own longitudinal study of "recreational athletes" resulted in an approximately 6% increase in tHb over the course of 9 months of endurance training, suggesting Training adjusts tHb and tEV slowly, and significant increases may require years of training.
Sedentary high-altitude residents have elevated tHb compared with low-altitude residents, and blood volume was found to increase from ~80 to ~100 ml/kg in low-altitude residents (Hurtado, 1964; Sanchez et al., 1970). Results from high-altitude sojourners suggest that, similar to training, increases in tHb and blood volume are slow, requiring weeks to months of high-altitude exposure. At high altitudes, this increase may be masked by a decrease in PV. Therefore, short-term stays at moderate and high altitudes do not increase tHb and tEV. A summary of different studies showed that some found no change in tEV with ascent, while some found differences that were explained by differences in duration of exposure to high altitude. When the stay lasted approximately 3 weeks, tEV was found to increase by 62 to 250 ml per week.
Based on the increase in tEV upon ascent to high altitude and training in normoxia, it was concluded that the effects of training and high altitude exposure on tHb are likely to be additive and significant at simulated altitude or ascent to moderate or high altitude. of training should result in an increase even greater than training in normoxia. However, the results were inconsistent, ranging from no effects to significant increases after 3-4 weeks of training at altitudes of 2100 to 2400 meters. Part of the reason for the lack of effect is that training at high altitudes is less intense than at lower altitudes, due to reduced performance with increasing altitude. Several strategies have been developed aimed at increasing training efficiency while still "burning out" adjustments to hypoxia, one of which is the "sleep-high-train-low" protocol. Current concepts and concerns are reviewed in . The results are unclear and there is generally no effect on tHb. A comprehensive analysis showed that exposure to hypoxia for more than 14 hours per day appears to be required to produce significant increases in tHb and tEV.
Control of Erythropoiesis Bert had recognized that living at high altitudes corresponded with increases in hemoglobin and later Hct, Hb and tHb, later thought to be associated with increased erythropoietin levels. When inspired PO2 is low, the elevated tEV is thought to compensate for the reduced arterial O2 content. Vascular endothelial growth factor VEGF stimulates blood vessel formation is another method of ensuring tissue O2 supply in chronic hypoxia. Both processes rely on specific signaling pathways that sense hypoxia within typical target cells and regulate the expression of specific genes.
One such oxygen-dependent mechanism is through the controlled expression of hypoxia-inducible factor HIF. Active HIF consists of α and β subunits. The beta subunit (HIF-β, also known as ARNT) is constitutively expressed and is not directly affected by oxygen levels. There are several isoforms of the α subunit, of which HIF-1α appears to primarily control metabolic regulation such as glycolysis, while HIF-2α has been identified as the major regulator of erythropoiesis. Under hypoxic conditions, hydroxylation of the HIF-α subunit by prolyl hydroxylase (PDH) is blocked due to lack of O 2 , which is required as a direct substrate and then blocks the Van Hippel-Lindau tumor suppressor pVHL-E3 Hydroxylation-dependent polyubiquitination by ligases and subsequent proteasomal degradation results in increased protein levels of HIF alpha subunits. After stabilization, α subunits enter the nucleus, where they dimerize with HIF-β. The dimer binds to a specific base sequence in the gene promoter region called the hypoxia response element HRE to induce gene expression. In addition to stabilization, HIF-α subunits are also controlled at the transcriptional level.
It is summarized that HIF-2α is the main regulator of EPO production by the liver (fetus) and kidney (adult), but there are also various direct and indirect mechanisms. Although it was related to the effects of HIF-1α rather than HIF-2α at that time, it can be seen that hypoxia-controlled gene expression not only regulates the expression of EPO, but also regulates the expression of EPO. Proteins whose role is a prerequisite for erythropoiesis, such as EPO receptors, ferroportins that mediate intestinal iron reabsorption, and transferrin and transferrin receptors required for iron transport to peripheral cells.
In adults, the oxygen sensors that control EPO production are located in the kidney, where the EPO-producing cells have been shown to be peritubular fibroblasts in the renal cortex. The production of EPO can be induced by two types of hypoxia: one is that PO2 is reduced in the kidneys and other tissues while the hemoglobin concentration is normal, such as hypoxia and hypoxia. The other is called anemic hypoxia, in which hemoglobin concentration is reduced but arterial PO2 is normal, resulting in reduced venous PO2. There appears to be no difference in the effectiveness of producing EPO in either case. The mixture of these conditions may result in reduced blood flow to the kidneys at normal PO and hemoglobin concentrations, which should also result in reduced capillary and venous PO. The exact mechanisms controlling EPO production by fibroblasts are not fully understood but appear to involve hypoxia-dependent recruitment of fibroblasts located near the medulla and cortex.
EPO released into the blood has many functions besides stimulating red blood cell production. In the bone marrow, EPO binds to EPO receptors on erythroid island progenitor cells, where it stimulates proliferation and prevents apoptotic destruction of newly formed cells. This increases the amount of red blood cells released from the bone marrow each time, leading to an increase in tEV when the rate of release exceeds red blood cell destruction.
Effects of Exercise and Training on Erythropoiesis Increases in tHb and tEV in trained athletes indicate that exercise stimulates erythropoiesis. Another sign is an increase in reticulocyte count, which can be observed 1-2 days after endurance training and strength training units. Despite the apparent effect of a single training unit on red blood cell production, multiple studies have shown that reticulocyte counts in athletes are not significantly different from sedentary controls, and values appear to be fairly stable over the years. However, reticulocyte counts in athletes vary significantly throughout the year, with reticulocyte counts typically being higher at the beginning of the season but lower during intensive training, competition, and at the end of the season. However, markers of premature forms of reticulocytes were increased in athletes, indicating stimulated bone marrow.
Although the control of erythropoiesis in hypoxic and anemic hypoxia is well understood, the signals that stimulate erythropoiesis during training under normoxic conditions are less clear. Exposure to hypoxia causes a rapid increase in EPO, but no or only slight changes in EPO are observed in untrained and trained individuals following different types of exercise, whereas the time course of reticulocyte count changes is consistent with high altitude. The impact is similar. Higher reticulocyte count, lower mean erythrocyte buoyant density and mean erythrocyte hemoglobin concentration, and increased levels of other markers of lower mean erythrocyte age (higher 2,3-DPG and P50, higher erythrocyte enzyme activity and creatine) have been found in the peripheral blood of trained individuals and are indicators of increased red blood cell turnover thereby stimulating erythropoiesis. These newly formed red blood cells facilitate the passage of blood through capillaries because they have greater membrane fluidity and deformability.
Arguments regarding hypoxia as a relevant trigger for exercise-induced erythropoiesis are sparse and indirect at best. Even during strenuous exercise, there is only a small decrease in arterial PO, which by itself is rarely sufficient to cause associated renal EPO production. However, as exercise intensity increases, renal blood flow decreases significantly, which reduces renal O2 supply. The O2 supply to the renal tubules may be further reduced because renal cortical arteries and veins run in parallel, allowing O2 exchange diffusion which may lead to arterial deoxygenation. PO in cortical veins is lower due to the high oxygen consumption required for Na+ and water reabsorption by renal cortical epithelial cells. It can therefore be speculated that reduced flow during exercise further reduces renal cortical PO to levels that cause significant peritubular hypoxia in EPO-producing fibroblasts during exercise, and that this effect is exacerbated with increasing exercise intensity. Interestingly, training attenuated the reduction in renal blood flow that appeared to be more pronounced after endurance than high-intensity interval sprint training in rats, which may explain the weaker erythropoietic response in trained athletes.
Several humoral factors known to influence erythropoiesis also change during exercise. Androgens have long been known for their stimulatory effects on erythropoiesis through stimulation of EPO release, increased bone marrow activity, and iron incorporation into red blood cells, best illustrated by polycythemia following androgen therapy. Endurance exercise and resistance training can cause temporary increases in testosterone levels in both men and women. Post-exercise values vary with exercise intensity in both sexes. Interestingly, post-exercise testosterone levels also vary directly with mood, which appears to be more pronounced in men than women.
Stress hormones such as catecholamines and cortisol stimulate the release of reticulocytes from the bone marrow and may enhance erythropoiesis. Erythropoiesis is also stimulated by growth hormone and insulin-like growth factors, which also increase during exercise.
Reduced Hct in athletes is termed "exercise anemia". It has long been interpreted as increased destruction of red blood cells during exercise and thus appears to be identical to the well-known phenomenon of hemoglobinuria in trimester. Intravascular destruction of red blood cells occurs under shear stresses between 1000 and 4000 dyn/cm, values well above physiological values at rest. It has to do with the intensity and type of exercise. Runner's foot strike is the most common cause of intravascular hemolysis, which can be prevented with good insoles. It also occurs in mountain climbing, strength training, karate, swimmers, basketball, kendo fencing, and drummers. Running exercise has been found to increase plasma hemoglobin from approximately 30 mg/L at rest to approximately 120 mg/L, indicating that approximately 0.04% of all circulating red blood cells are lysed. Exercise has been shown to alter the appearance of red blood cell membranes associated with elevated haptoglobin. Aged erythrocytes may be particularly susceptible to exercise-induced intravascular hemolysis, as manifested by reduced mean erythrocyte buoyant density, and density distribution curves skewed toward younger, less dense cells in trained individuals, as manifested by increased levels of pyruvate kinase activity , 2,3-DPG and P 50, higher reticulocyte count. Other possible causes of "exercise anemia" being discussed are nutritional, such as insufficient protein intake and changes in blood lipids and iron deficiency.
in conclusion
There are many mechanisms that contribute to increasing tissue oxygen supply during exercise. During exercise, the increase in skeletal muscle O2 demand is primarily matched by an increase in muscle blood flow by increasing cardiac output, regulating blood flow distribution between active and inactive organs, and optimizing microcirculation. Red blood cells support local blood flow by providing the vasodilator NO through direct conversion from nitrate and through the release of ATP, which causes endothelial NO release. In any given capillary blood flow, the amount of O2 unloaded from Hb to working muscle cells can be greatly increased by lowering Hb-O2 affinity. This occurs when cells enter the capillaries that supply muscle cells, where they are exposed to elevated temperatures, H+, and CO2. Training further enhances O2 flux in working muscles at all levels of conditioning: it increases maximal cardiac output, improves blood flow to the muscles by stimulating vasculogenesis, and improves the rheological properties of red blood cells. Training increases total hemoglobin mass by stimulating red blood cell production, thereby increasing the amount of O2 the blood can carry. It also increases erythrocyte 2,3-DPG, thereby increasing Hb-O affinity sensitivity to acidification-dependent O-release. This system appears to be optimized for low-altitude exercise because in hypoxic environments the reduction in arterial PO, which is the main determinant of O diffusion, cannot be adequately compensated by the O transport mechanisms described above, resulting in performance that scales with the degree of hypoxia increases with the increase.
