Effect of hyperoxia on the oxyhemoglobin dissociation curve in various periods of aging

Gas composition of the arterial and venous blood and the oxyhemoglobin dissociation curve were determined before and after 20 minutes of oxygen inhalation in 9 apparently healthy subjects aged 60 to 74 years and in 9 young subjects aged 19 to 32 years. In hyperoxia of younger subjects, there was a shift to the left of both the oxyhemoglobin dissociation curve of the native blood and standard dissociation curve (pH 7.4). In old age, the shift to the left of the standard dissociation curve due to hypoxia was quite negligible and statistically insignificant, whereas in the native blood it was entirely absent because of the increased blood PCO2 and associated Bohr effect.     

Effect of nitrite-induced methemoglobinemia on the kinetics of blood deoxygenation

Kinetics of blood deoxygenation was studied during acute hypoxia induced by subcutaneous administration of sodium nitrite using polarographic method. Plasma oxygen tension remained unaltered as the dose of sodium nitrite increased, while the dynamics of oxygen release was dose-dependent. The constant of oxyhemoglobin deoxygenation rate proved to vary with blood deoxygenation. The nitrite-induced deceleration of oxyhemoglobin deoxygenation was due to the inactivation of a fraction of hemoglobin as well as to the increased hemoglobin oxygen affinity and possible changes in the oxygen permeability of erythrocyte membranes during acute methemoglobinemia.     

Mechanism of the antihypoxic action of zinc compounds

It was established in experimental normobaric and hypobaric hypoxia and hemic hypoxia induced by carbon monoxide poisoning that zinc compounds administered in a dose of 0.15 mA/kg have a marked prophylactic protective effect. The mechanism of action of zinc compounds consists in changes of oxygen transport blood function. It was shown that interaction of the hemoglobin molecule with zinc ion brings about an increase in Hb affinity for O2 (the left drive of the oxyhemoglobin dissociation curve), a reduction in cooperative interaction of hemoglobin subunits, and a relative decrease in hemoglobin affinity for carbon monoxide. The leading defence mechanism against hypoxic hypoxia is the left drive, the mechanism of defence against carbon monoxide protection consists in the lowering of the "hem-hem" cooperation and of the relative hemoglobin affinity for carbon monoxide.     

Differences in the strategies and potentials of human adaptation to hypoxia

The general patterns and individual specific features of human adaptation to acute hypoxic hypoxia caused by breathing a hypoxic oxygen-nitrogen gas mixture containing 8.0% oxygen have been studied. It was found that, at the initial stage of hypoxia, all examined subjects demonstrated a reduced oxygen consumption as compared to normoxia; then, this parameter increased and, beginning from a certain moment (after 5–15 min of exposure), exceeded the baseline level by 10–40%. Hypotheses explaining the mechanisms of this growth in oxygen consumption during hypoxia are considered. It has been found that the roles of the cardiovascular system and mechanisms of the tissue and cellular utilization of oxygen in the growth of the rate of oxygen consumption caused by hypoxia vary in different subjects. The hypothesis is put forward that the relatively low potential for rearrangement of the biological oxidation system at the cellular level, aimed at increasing the rate of oxygen consumption, predetermines a need to increase the rate of oxygen supply by the blood and, therefore, a greater strain of the cardiovascular system. In many cases, this strain can cause failure of adaptation to hypoxia. Other parameters that can serve as characteristics of a subject’s resistance to hypoxia, such as the intensity of EEG slow waves and the level of blood oxygenation, are also considered.     

The increase of carbon dyoxidi production at hypoxia in health subjects

Pulmonary gas exchange, SpO2 and heart rate at 15-min hypoxia (respiration by air with 0.17; 0.15 and 0.13 oxygen fractions) have been investigated in 24 health subjects. It has been established, results of the group analysis and the results of the individual analysis had been differed. Reaction on hypoxia at the group analysis had been found only at 0.13 02 fraction. It was only hyperventilation. The individual analysis had revealed 4 types of reaction on hypoxia already at 0.17 and 0.15 02 fractions: (1) hyperventilation, (2) decrease of oxygen consumption, (3) increase of ventilation effectiveness, (4) increase of CO2 production. The mechanisms of last reaction are unknown, but we supposed it was connected with anaerobic metabolism. The reactions were detected at light hypoxia (0.17 and 0.15 oxygen fractions) in 90% health subjects when SpO2 decreased to 87-93%. The increase ventilation has been detected at hypoxia within respiration 0.13 oxygen in 60% subjects when SpO2 decreased to 83-87%, while other reactions were nearly absent.     

The respiratory function of blood in elderly and old age and the factors that determine it

Indices of pulmonary gas exchange, blood gases, the oxyhemoglobin dissociation curve, and intraerythrocytic metabolic parameters were analyzed in 62 apparently healthy elderly and senile subjects (60–92 years old) and 18 young healthy subjects (19–30 years old). PaO₂ was found to decrease in elderly and senile subjects. Arterial hypoxemia in old age is caused by an increase in the alveoloarterial PO₂ gradient, primarily as a result of the malcoordination of pulmonary ventilation and blood flow. A rightward compensatory shift of the oxyhemoglobin dissociation curve was observed, which was due to facilitated oxygen release in tissues owing to a pH decrease in erythrocytes (the Bohr effect). However, the facilitated oxygen release by oxyhemoglobin cannot compensate for the effect of factors deteriorating oxygen supply delivery to tissues, observed with aging, which is confirmed by the decrease in the partial pressure of oxygen in the venous blood of elderly and senile people, reflecting PO₂ in tissues.     

Polymerized bovine hemoglobin decreases oxygen delivery during normoxia and acute hypoxia in the rat

Hemoglobin-based oxygen carriers (HBOC) have been primarily studied for blood loss treatment. More recently infusions of HBOC in euvolemic subjects have been proposed for a wide variety of potential therapies in which increased tissue oxygenation would be beneficial. However, compared with the exchange transfusion models to study blood loss, less is known about HBOC oxygen delivery and vasoacitvity when it is infused in euvolemic subjects. We hypothesized that HBOC [polymerized bovine hemoglobin (PBvHb)] infusion creating hypervolemia would increase oxygen delivery to tissues during acute global hypoxia. Vascular oxygen content and hemodynamics were determined after euvolemic rats were infused with 3 ml of either lactated Ringer or PBvHb solution (13 g/dl, 1.3 g/kg) during acute hypoxia (FIO2 = 10%, 4 h) or normoxia (FIO2 = 21%) exposure. Our data demonstrated that compared with Ringer-infused animals, in hypoxia and normoxia, PBvHb treatment improved oxygen content but raised mean arterial pressure, lowered stroke volume, heart rate, and cardiac index, which resulted in a net reduction in blood flow and oxygen delivery to the tissues. The PBvHb vasoactive effect was similar in magnitude and direction as to the Ringer-infused animals treated with a nitric oxide synthase inhibitor nitro-l-arginine, suggesting the PBvHb effect is mediated via nitric oxide scavenging. We conclude that infusion of PBvHb is not likely to be useful in treating global hypoxia under these conditions.     

Cerebral oxygen availability by NIR spectroscopy during transient hypoxia in humans

The effects of mild hypoxia on brain oxyhemoglobin, cytochrome a,a3 redox status, and cerebral blood volume were studied using near-infrared spectroscopy in eight healthy volunteers. Incremental hypoxia reaching 70% arterial O2 saturation was produced in normocapnia [end-tidal PCO2 (PETCO2) 36.9 +/- 2.6 to 34.9 +/- 3.4 Torr] or hypocapnia (PETCO2 32.8 +/- 0.6 to 23.7 +/- 0.6 Torr) by an 8-min rebreathing technique and regulation of inspired CO2. Normocapnic hypoxia was characterized by progressive reductions in arterial PO2 (PaO2, 89.1 +/- 3.5 to 34.1 +/- 0.1 Torr) with stable PETCO2, arterial PCO2 (PaCO2), and arterial pH and resulted in increases in heart rate (35%) systolic blood pressure (14%), and minute ventilation (5-fold). Hypocapnic hypoxia resulted in progressively decreasing PaO2 (100.2 +/- 3.6 to 28.9 +/- 0.1 Torr), with progressive reduction in PaCO2 (39.0 +/- 1.6 to 27.3 +/- 1.9 Torr), and an increase in arterial pH (7.41 +/- 0.02 to 7.53 +/- 0.03), heart rate (61%), and ventilation (3-fold). In the brain, hypoxia resulted in a steady decline of cerebral oxyhemoglobin content and a decrease in oxidized cytochrome a,a3. Significantly greater loss of oxidized cytochrome a,a3 occurred for a given decrease in oxyhemoglobin during hypocapnic hypoxia relative to normocapnic hypoxia. Total blood volume response during hypoxia also was significantly attenuated by hypocapnia, because the increase in volume was only half that of normocapnic subjects. We conclude that cytochrome a,a3 oxidation level in vivo decreases at mild levels of hypoxia. PaCO is an important determinant of brain oxygenation, because it modulates ventilatory, cardiovascular, and cerebral O2 delivery responses to hypoxia.     

Age-Related Peculiarities of the Control of Respiration and Their Correlation with the Intensity of Free-Radical Processes

We describe the results of a study of the relations between the control of the respiratory function in isocapnic increasing hypoxia and the intensity of free-radical processes in groups of healthy young and aged subjects. It is known that aging is accompanied by some weakening of the response of the respiratory system to hypoxia with no considerable changes in the indices of ventilation in the resting state. Aged subjects, as compared with young tested persons, are characterized by a decrease in the activity of catalase, the absence of significant differences in the activity of superoxide dismutase, and a trend toward an increase in the content of products of lipid peroxidation in the blood. We discuss possible mechanisms mediating age-related modifications in the system of control of respiration and consider shifts in the system of pro/antioxidant balance and intensification of peroxidation processes against the background of a decreased activity of catalase primary changes responsible for the above modifications. These effects lead to modifications of the sensitivity of chemoreceptors responding to a drop in O₂ tension in the blood.     

External respiration response of trained skiers to intermittent normobaric hypoxia

As part of a study on the resistance of subjects adapted to aerobic physical activity to hypoxia, the ventilatory response of trained skiers whose regular physical training is associated with hyperventilation to intermittent normobaric hypoxia has been analyzed. A test session consisted of three cycles of breathing alternately a hypoxic gas mixture (10 vol % O₂) for 5 min and normal air for 5 min. The skiers have a lower oxygen consumption rate as compared with untrained subjects, i.e., a reduced resistance to hypoxia. Therefore, the efficiency of respiration during hypoxia is lower in atheltes, which is caused by a rapid decrease in blood oxygenation, whereas during breathing normal atmospheric air, the efficiency of respiration is lower in untrained subjects.     

Respiratory control in humans after 8 h of lowered arterial PO2, hemodilution, or carboxyhemoglobinemia.

In humans exposed to 8 h of isocapnic hypoxia, there is a progressive increase in ventilation that is associated with an increase in the ventilatory sensitivity to acute hypoxia. To determine the relative roles of lowered arterial PO2 and oxygen content in generating these changes, the acute hypoxic ventilatory response was determined in 11 subjects after four 8-h exposures: 1) protocol IH (isocapnic hypoxia), in which end-tidal PO2 was held at 55 Torr and end-tidal PCO2 was maintained at the preexposure value; 2) protocol PB (phlebotomy), in which 500 ml of venous blood were withdrawn; 3) protocol CO, in which carboxyhemoglobin was maintained at 10% by controlled carbon monoxide inhalation; and 4) protocol C as a control. Both hypoxic sensitivity and ventilation in the absence of hypoxia increased significantly after protocol IH (P < 0.001 and P < 0.005, respectively, ANOVA) but not after the other three protocols. This indicates that it is the reduction in arterial PO2 that is primarily important in generating the increase in the acute hypoxic ventilatory response in prolonged hypoxia. The associated reduction in arterial oxygen content is unlikely to play an important role.     

Changes of external respiration, brain circulation and the EEG in acute hypoxia in the subjects with different hypoxic resistance

Two groups of individuals were distinguished in experiments with acute hypoxic action (respiration of oxygen-nitrogen mixture with 8 % oxygen content) - with low (LHR) and high (HHR) resistance to hypoxia. In subjects of the LR group, slowing down of the pulse rate and lowering of arterial pressure in the shoulder artery were observed on the 5th-10th minute of hypoxia. In the HHR subjects, primary growth of the pulse rate was followed by its stabilization; no significant changes of the arterial pressure were observed. In LHR subjects, in the first 5-10 min of the hypoxia, a significantly lower level of the blood oxygen saturation was observed in comparison to the HHR. In the LHR group, there was a higher increment of amplitude-frequency index of the rheoencephalogram in comparison to the HHR, indicating a higher increment of the cerebral blood flow. The slowing down of the pulse rate in the LHR subjects was accompanied with increasing cerebral pulse volume, so that in spite of the pulse rate slowing, the minute volume of cerebral circulation increased. In the LHR subjects, two-phased dynamics of the EEG was observed: in the first phase there was a slow growth of theta- and delta-band EEG spectral power, in the second phase (on the 5th-10th min of hypoxia), sharp (200-300 % of the background level) growth of the EEG spectral power in those bands was observed. In the HHR subjects, gradual growth of EEG spectral power occurred with relative stabilization on the 10th-12th min of hypoxia. Possible role of the stress in the collapse-like reaction during acute hypoxia is analysed, which might cause increase of the oxygen request of the brain, higher growth of cerebral blood flow and more pronounced lowering of functional activity of the brain in the LHR subjects.     

Involvement of oxygen-depending processes in the pathogenesis of hepatic reperfusion injury

The disbalance between reactive oxygen species generation and antioxidant defensive factors importantly contributes in the development of hepatic reperfusion damage. Changes in blood oxygen transport during hepatic ischemia/reperfusion are involved in its development. Ischemia-induced oxyhemoglobin dissociation curve shift rightwards also exists during the hepatic reperfusion and thereby may facilitate the free radical attacks against the liver. The least disorders in blood oxygen transport, prooxidant-antioxidant balance and hepatic morpho-functional state were observed during the postischemic period under the conditions of moderate hypoxia. The protective effect of L-arginine during the hepatic ischemia-reperfusion may be partially due to the changed hemoglobin function and thereby tissue oxygen delivery and to the keeping of body prooxidant-antioxidant balance. The development of new pharmacological tools to modify the blood oxygen transport and generate the optimal nitric oxide amounts may be a promising strategy for correction of reperfusion injury.     

Individual specifics of oxygen consumption by the human organism in hypoxia

Influence of hypoxia on a human organism was studied with the help of hypoxic gas mixtures (HGM) in the first series with 14 % content of oxygen in nitrogen (n = 6), in the second one--with 12 % (n = 10) in the third one--with 8 % (n = 14). Hypoxic exposition in all the series was 25 min. In 6 subjects engaged in all the 3 series, physical working capacity was assessed in two-step test on a veloergometer. In all the 3 series, oxygen consumption by the organism some time after the start of the hypoxic action exceeded the background normnoxic level. Maximal value of this excess on the average was the highest in HGM-12 series--40 +/- 12 %. Maximal increase of the respiration and central blood circulation velocity was the highest in HGM-8 series, 90 +/- 24 and 25 +/- 16 % respectively. Analysis of the EEG parameters, oxygen saturation and rheoencephalographic data indicates the probability of the cerebral metabolic rate of oxygen during hypoxia to beein normal (in most subjects) and even increased (in some subjects). In 3 subjects of 6, whose physical working capacity was assessed, maximal increase of oxygen consumption was observed in HGM-8 series--105 +/- 34 %. Their physical working capacity was higher than of those subjects, who showed maximal increase of oxygen consumption in HGM-12 series. Analysis of increase in oxygen consumption (paradoxical under hypoxic conditions) doesn't allow to ascribe it wholly to an increase of the respiration and central blood circulation. Obviously, the increase of oxygen and energy expenditures for biochemical adaptation to hypoxia, which has common features with adaptation to physical activity plays an important role under hypoxia.     

Nitric oxide formation from the reaction of nitrite with carp and rabbit hemoglobin at intermediate oxygen saturations

The nitrite reductase activity of deoxyhemoglobin has received much recent interest because the nitric oxide produced in this reaction may participate in blood flow regulation during hypoxia. The present study used spectral deconvolution to characterize the reaction of nitrite with carp and rabbit hemoglobin at different constant oxygen tensions that generate the full range of physiological relevant oxygen saturations. Carp is a hypoxia-tolerant species with very high hemoglobin oxygen affinity, and the high R-state character and low redox potential of the hemoglobin is hypothesized to promote NO generation from nitrite. The reaction of nitrite with deoxyhemoglobin leads to a 1 : 1 formation of nitrosylhemoglobin and methemoglobin in both species. At intermediate oxygen saturations, the reaction with deoxyhemoglobin is clearly favored over that with oxyhemoglobin, and the oxyhemoglobin reaction and its autocatalysis are inhibited by nitrosylhemoglobin from the deoxyhemoglobin reaction. The production of NO and nitrosylhemoglobin is faster and higher in carp hemoglobin with high O(2) affinity than in rabbit hemoglobin with lower O(2) affinity, and it correlates inversely with oxygen saturation. In carp, NO formation remains substantial even at high oxygen saturations. When oxygen affinity is decreased by T-state stabilization of carp hemoglobin with ATP, the reaction rates decrease and NO production is lowered, but the deoxyhemoglobin reaction continues to dominate. The data show that the reaction of nitrite with hemoglobin is dynamically influenced by oxygen affinity and the allosteric equilibrium between the T and R states, and that a high O(2) affinity increases the nitrite reductase capability of hemoglobin.     

Blood pressure response to chronic episodic hypoxia: the renin-angiotensin system.

By using an inspired oxygen fraction that produces oxyhemoglobin desaturation equivalent to that seen in human sleep apnea, we have demonstrated that 35 days of recurrent episodic hypoxia (every 30 s for 7 h/day) results in an 8-13 mmHg persistent increase in diurnal systemic mean arterial blood pressure (MAP) in rats. Blockade of angiotensin II receptors (AT(1a)) eliminates this response. Separate groups of male Sprague-Dawley rats were fed high-salt (8%), ad libitum-salt, or low-salt (0.1%) diets for 7 wk: 2 wk of wash-in for baseline blood pressure measurement and 5 wk of experimental conditions. Rats in each salt group were subjected to episodic hypoxia whereas controls remained unhandled under normoxic conditions. MAP remained at basal levels in all nonepisodic hypoxia controls as well as high-salt-diet episodic hypoxia-exposed rats. Ad lib and low-salt episodic hypoxia rats showed an increase in MAP from 106 and 104 mmHg at baseline to 112 and 113 mmHg, respectively (P < 0.05). Whole kidney renin mRNA was suppressed in high-salt controls and episodic hypoxia rats, whereas kidney AT(1a) mRNA showed opposite changes. Suppression of the renin-angiotensin system with a high-salt diet blocks the increase in MAP in episodic hypoxia-challenged rats, in part by suppressing local tissue renin levels. Upregulation of the tissue angiotensin II system appears to be necessary for the chronic blood pressure changes that occur from episodic hypoxia.     

The sensitivity of hemoglobin oxygen affinity to diphosphoglycerate and the characteristic pH of methemoglobin.

The sensitivity of the oxygen affinity of a hemoglobin to 2,3-diphosphoglyceric acid concentration has been defined as the change in log1/2O2 (deltalogp1/2O2) which results from saturating the hemoglobin with 2,3-diphosphoglyceric acid. The sensitivity varies from one hemoglobin species to another and is linearly rated to the difference in the logarithm of the binding constants of 2,3-diphosphoglyceric acid to deoxy- and oxyhemoglobin, the characteristic pH (pHch), and inversely proportional to the magnitude of the alkaline Bohr effect measured in a saturating amount of 2,3-diphosphoglyceric acid. Its magnitude is higher in large animals than in small animals and varies linearly with the charged amino acid composition of the hemoglobin. The charged amino acid residues must have been selected for in mammals with high metabolic needs and against in animals with low metabolic needs. Variability in the effect of 2,3-diphosphoglyceric acid on the oxygen transport in the different animal hemoglobins must therefore be the result of a positive Darwinian Selection of the charged amino acid residues in their hemoglobins. Furthermore, all the charged groups and not those at the binding site alone, affect the 2,3-diphosphoglyceric acid binding constant of a hemoglobin.     

Electrical activity of the brain and oxygen supply for cognitive-mnestic activity in humans under different degrees of hypoxia

Comparative analysis of the indices of oxygen supply for the body and the brain and the functional state of the brain was carried out in three experimental situations: performance of cognitive-mnestic tests under normoxic (TN) and hypoxic conditions (TH) and exposure to hypoxia in the absence of cognitive tasks (H). Each subject participated in all of the experiments. Hypoxic conditions were created by breathing of a hypoxic gas mixture (HGM) consisting of oxygen and nitrogen for 25 min. The first group (eight subjects) was exposed to moderate hypoxia, with the gas mixture containing 12% O₂ (HGM-12); the second group (eight subjects) was exposed to severe hypoxia, with the gas mixture containing 8% O₂ (HGM-8). The cognitive-mnestic activity (CMA) under both normoxia and hypoxia was continuous and included the following tests: “Arithmetic calculations,” “Memory for numerals,” “Colored figures”, and “Sensorimotor response time.” The CMA efficiency was significantly impaired only under severe hypoxia (HGM-8). The CMA efficiency was higher in some subjects of the first group (HGM-12) in the TH series as compared to that in the TN series. The EEG spectral power (SP) during CMA was decreased as compared to the background in all subjects in the TN series and in most subjects of the first group, exposed to HGM-12, whereas it was increased in all subjects of the second group, exposed to HGM-8. The EEG SP was lower in most subjects of both groups studied in the TH series as compared to that found in the H series. The rheographic index of cerebral blood flow rate was not changed compared to the background in the TN series and was increased in the H and TH series during HGM-8 treatment. The increase in cerebral blood flow was less pronounced in the TH series as compared to the H series in most subjects of the second group (HGM-8). Oxygen consumption by the body was elevated by 10–20% in the TN series. A significant increase in oxygen consumption was found in the subjects of both groups studied during hypoxia treatment (H), and it was greater in HGM-12. The following differences were found between the subjects of the two experimental groups: the increase in oxygen consumption in most subjects of the first group (HGM-12) was higher in the TH series as compared to the H series, whereas, in most subjects of the second group (HGM-8), the increase in oxygen consumption was higher in the H series. The data are discussed from the point of view of synergic and concurrent relationships between different forms of energy expenditure on structural and functional reorganization and organ-specific functions.     

Blood oxygen transport in rats under hypothermia combined with modification of the L-Arginine-NO pathway.

Nitric oxide (NO) has high affinity to heme and by interaction with oxyhemoglobin (HbO2) is converted into nitrate to form methemoglobin (MetHb) as a side product. In combining with deoxy-Hb NO yields a stable molecule of nitrosyl-hemoglobin (HbFe(II)NO) that can further be converted into nitrate and hemoglobin (Hb). In addition, Hb was shown to transport NO in a form of S-nitrosohemoglobin (SNO-Hb). These features of the Hb and NO interaction are important for blood oxygen transport including hemoglobin-oxygen affinity (HOA). The present investigation was aimed to study the blood oxygen transport indices (pO2, pCO2, pH, HOA, etc.) in rats under hypothermia combined with a modification of L-arginine-NO pathway. To modify the L-arginine-NO pathway, rats were administered with N(G)-nitro-L-arginine methyl ester (L-NAME), L-arginine, or sodium nitroprusside (SNP) intravenously before cooling. A substantial impairment of oxygen delivery and development of hypoxia, with an important contribution of HOA into the latter accompanied the deep hypothermia in rats. All the experimental groups developed metabolic acidosis, less pronounced in rats treated with L-arginine only. In the experiments with a modification of the L-arginine-NO pathway, an enhanced cold resistance, attenuated oxygen deficiency, and a weaker oxyhemoglobin dissociation curve (ODC) shift leftwards were observed only after the administration of L-arginine. Neither SNP nor L-NAME had not any protective effects. L-Arginine lowered the value of standard P50 (pO2, corresponding to 50% Hb saturation with oxygen at 37 degrees C, pH 7.4, and pCO2 = 40 mmHg). The actual P50 (at actual pH, pCO2 and temperature) decreased by approximately 15 mmHg and was significantly higher than that under hypothermia without the drug treatment (21.03 +/- 0.35 vs 17.45 +/- 0.60 mmHg). NO also can contribute to this system through different mechanisms (HOA modification, vascular tone regulation, peroxynitrite formation, and effects).     

Effect of acute hypoxia on microcirculatory and tissue oxygen levels in rat cremaster muscle.

Repeated exposure to brief periods of hypoxia leads to pathophysiological changes in experimental animals similar to those seen in sleep apnea. To determine the effects of such exposure on oxygen levels in vivo, we used an optical method to measure PO2 in microcirculatory vessels and tissue of the rat cremaster muscle during a 1-min step reduction of inspired oxygen fraction from 0.21 to 0.07. Under control conditions, PO2 was 98.1 +/- 1.9 Torr in arterial blood, 52.2 +/- 2.8 Torr in 29.0 +/- 2.7-microm arterioles, 26.8 +/- 1.7 Torr in the tissue interstitium near venous capillaries, and 35.1 +/- 2.6 Torr in 29.7 +/- 1.9-microm venules. The initial fall in PO2 during hypoxia was significantly greater in arterial blood, being 93% complete in the first 10 s, whereas it was 68% complete in arterioles, 47% at the tissue sites, and 38% in venules. In the 10- to 30-s period, the fall in normalized tissue and venular PO2 was significantly greater than in arterial PO2. At the end of hypoxic exposure, PO2 at all measurement sites had fallen very nearly in proportion to that in the inspired gas, but tissue oxygen levels did not reach critical PO2. Significant differences in oxyhemoglobin desaturation rate were also observed between arterial and microcirculatory vessels during hypoxia. In conclusion, the fall in microcirculatory and tissue oxygen levels in resting skeletal muscle is significantly slower than in arterial blood during a step reduction to an inspired oxygen fraction of 0.07, and tissue PO2 does not reach anaerobic levels.