Blood volume versus deoxygenated NIRS signal: computational analysis of the effects muscle O2 delivery and blood volume on the NIRS signals.

Near-infrared spectroscopy (NIRS) signals quantify the oxygenated (ΔHbMbO2) and deoxygenated (ΔHHbMb) heme group concentrations. ΔHHbMb has been preferred to ΔHbMbO2 in evaluating skeletal muscle oxygen extraction because it is assumed to be less sensitive to blood volume (BV) changes, but uncertainties exist on this assumption. To analyze this assumption, a computational model of oxygen transport and metabolism is used to quantify the effect of O2 delivery and BV changes on the NIRS signals from a canine model of muscle oxidative metabolism (Sun Y, Ferguson BS, Rogatzki MJ, McDonald JR, Gladden LB. Med Sci Sports Exerc 48: 2013-2020, 2016). The computational analysis accounts for microvascular (ΔHbO2, ΔHHb) and extravascular (ΔMbO2, ΔHMb) oxygenated and deoxygenated forms. Simulations predicted muscle oxygen uptake and NIRS signal changes well for blood flows ranging from resting to contracting muscle. Additional NIRS signal simulations were obtained in the absence or presence of BV changes corresponding to a heme groups concentration changes (ΔHbMb = 0-48 µM). Under normal delivery (Q = 1.0 L·kg-1·min-1) in contracting muscle, capillary oxygen saturation (So2) was 62% with capillary ΔHbO2 and ΔHHb of ± 41 µΜ for ΔHbMb = 0. An increase of BV (ΔHbMb = 24 µΜ) caused a ΔHbO2 decrease (16µΜ) almost twice as much as the increase observed for ΔHHb (9 µΜ). When So2 increased to more than 80%, only ΔHbO2 was significantly affected by BV changes. The analysis indicates that microvascular So2 is a key factor in determining the sensitivity of ΔHbMbO2 and deoxygenated ΔHHbMb to BV changes. Contrary to a common assumption, the ΔHHbMb is affected by BV changes in normal contracting muscle and even more in the presence of impaired O2 delivery.NEW & NOTEWORTHY Deoxygenated is preferred to the oxygenated near-infrared spectroscopy signal in evaluating skeletal muscle oxygen extraction because it is assumed to be insensitive to blood volume changes. The quantitative analysis proposed in this study indicates that even in absence of skin blood flow effects, both NIRS signals in presence of either normal or reduced oxygen delivery are affected by blood volume changes. These changes should be considered to properly quantify muscle oxygen extraction by NIRS methods.

Effect of Blood Flow on Hemoglobin and Myoglobin Oxygenation in Contracting Muscle Using Near-Infrared Spectroscopy.

Insufficient O2 delivery to, and uptake by skeletal muscle can produce mobility limitations for patients with chronic diseases. Near-infrared spectroscopy (NIRS) can be used to noninvasively quantify the balance between skeletal muscle O2 delivery and utilization during contraction. However, it is not clear how the oxygenated or deoxygenated NIRS signal should be used to assess muscle O2 changes. This issue is related to the fact that the contributions of hemoglobin (Hb) and myoglobin (Mb) cannot be distinguished. This conundrum can be resolved by quantitative analysis of experimental data by computer simulations with a mechanistic, mathematical model. Model simulations distinguish dynamic responses of the oxygenated (HbO2, MbO2) and deoxygenated (HHb, HMb) contributions to the NIRS signal components (HbMbO2, HHbMb). Simulations of muscle O2 uptake and NIRS kinetics correspond closely to published experimental data (Hernández et al., J Appl Physiol 108: 1169-1176, 2010). Simulated muscle O2 uptake and oxygenation kinetics with different blood flows indicate (1) faster O2 delivery is responsible for slower muscle oxygenation kinetics; (2) Hb and Mb contributions to the HbMbO2 are similar (40-60%); and (3) Hb and Mb contributions to the HHbMb are significantly different, 80% and 20%, respectively. The effect of slow blood flow kinetics on oxygenated Hb and Mb contributions is minimal. However, the effect on the imbalance between O2 delivery and utilization rates causes significant overshoots and undershoots of deoxygenated Hb and Mb contributions. Model analysis in combination with NIRS measurements and information on hemodynamic and microvascular distribution can help to determine the use of NIRS signal in evaluating the factors limiting exercise tolerance in health and disease states.

A patient with acute liver failure and extreme hypoglycaemia with lactic acidosis who was not in a coma: causes and consequences of lactate-protected hypoglycaemia.

Lactate can substitute for glucose as a metabolic substrate. We report a patient with acute liver failure who was awake despite a glucose level of 0.7 mmol/l with very high lactate level of 25 mmol/l. The hypoglycaemia+hyperlactataemia combination may be considered paradoxical since glucose is the main precursor of lactate and lactate is reconverted into glucose by the Cori cycle. Literature relevant to the underlying mechanism of combined deep hypoglycaemia and severe hyperlactataemia was assessed. We also assessed the literature for evidence of protection against deep hypoglycaemia by hyperlactataemia. Four syndromes demonstrating hypoglycaemia+hyperlactataemia were found: 1) paracetamol-induced acute liver failure, 2) severe malaria, 3) lymphoma and 4) glucose-6-phosphatase deficiency. An impaired Cori cycle is a key component in all of these metabolic states. Apparently the liver, after exhausting its glycogen stores, loses the gluconeogenic pathway to generate glucose and thereby its ability to remove lactate as well. Several patients with lactic acidosis and glucose levels below 1.7 mmol/l who were not in a coma have been reported. These observations and other data coherently indicate that lactate-protected hypoglycaemia is, at least transiently, a viable state under experimental and clinical conditions. Severe hypoglycaemia+hyperlactataemia reflects failure of the gluconeogenic pathway of lactate metabolism. The existence of lactate-protected hypoglycaemia implies that patients who present with this metabolic state should not automatically be considered to have sustained irreversible brain damage. Moreover, therapies that aim to achieve hypoglycaemia might be feasible with concomitant hyperlactataemia.

Regulation of cellular gas exchange, oxygen sensing, and metabolic control.

Cells must continuously monitor and couple their metabolic requirements for ATP utilization with their ability to take up O2 for mitochondrial respiration. When O2 uptake and delivery move out of homeostasis, cells have elaborate and diverse sensing and response systems to compensate. In this review, we explore the biophysics of O2 and gas diffusion in the cell, how intracellular O2 is regulated, how intracellular O2 levels are sensed and how sensing systems impact mitochondrial respiration and shifts in metabolic pathways. Particular attention is paid to how O2 affects the redox state of the cell, as well as the NO, H2S, and CO concentrations. We also explore how these agents can affect various aspects of gas exchange and activate acute signaling pathways that promote survival. Two kinds of challenges to gas exchange are also discussed in detail: when insufficient O2 is available for respiration (hypoxia) and when metabolic requirements test the limits of gas exchange (exercising skeletal muscle). This review also focuses on responses to acute hypoxia in the context of the original "unifying theory of hypoxia tolerance" as expressed by Hochachka and colleagues. It includes discourse on the regulation of mitochondrial electron transport, metabolic suppression, shifts in metabolic pathways, and recruitment of cell survival pathways preventing collapse of membrane potential and nuclear apoptosis. Regarding exercise, the issues discussed relate to the O2 sensitivity of metabolic rate, O2 kinetics in exercise, and influences of available O2 on glycolysis and lactate production.

Increased steady-state VO2 and larger O2 deficit with CO2 inhalation during exercise.

AIM: To examine whether inhalation of CO(2) -enriched gas would increase steady-state VO(2) during exercise and enlarge O(2) deficit. METHODS: Ten physically active men (VO(2) 53.7 ± 3.6 mL min(-1) kg(-1) ; x ± SD) performed transitions from low-load cycling (baseline; 40 W) to work rates representing light (≈ 45% VO(2); 122 ± 15 W) and heavy (≈ 80% VO(2); 253 ± 29 W) exercise while inhaling normal air (air) or a CO(2) mixture (4.2% CO(2) , 21% O(2) , balance N(2) ). Gas exchange was measured with Douglas bag technique at baseline and at min 0-2, 2-3 and 5-6. RESULTS: Inhalation of CO(2) -enriched air consistently induced respiratory acidosis with increases in PCO(2) and decreases in capillary blood pH (P < 0.01). Hypercapnic steady-state VO(2) was on average about 6% greater (P < 0.01) than with air in both light and heavy exercise, presumably because of increased cost of breathing (ΔVE 40-50 L min(-1) ; P < 0.01), and a substrate shift towards increased lipid oxidation (decline in R 0.12; P < 0.01). VO(2) during the first 2 min of exercise were not significantly different whereas the increase in VO(2) from min 2-3 to min 5-6 in heavy exercise was larger with CO(2) than with air suggesting a greater VO(2) slow component. As a result, O(2) deficit was greater with hypercapnia in heavy exercise (2.24 ± 0.51 L vs. 1.91 ± 0.45 L; P < 0.05) but not in light (0.64 ± 0.21 L vs. 0.54 ± 0.20 L; ns). CONCLUSION: Inhalation of CO(2)-enriched air and the ensuing respiratory acidosis increase steady-state VO(2) in both light and heavy exercise and enlarges O(2) deficit in heavy exercise.

Prior heavy exercise eliminates VO2 slow component and reduces efficiency during submaximal exercise in humans.

We investigated the hypothesis that the pulmonary oxygen uptake (VO2) slow component is related to a progressive increase in muscle lactate concentration and that prior heavy exercise (PHE) with pronounced acidosis alters VO2 kinetics and reduces work efficiency. Subjects (n= 9) cycled at 75% of the peak VO2 (VO2peak) for 10 min before (CON) and after (AC) PHE. VO2 was measured continuously (breath-by-breath) and muscle biopsies were obtained prior to and after 3 and 10 min of exercise. Muscle lactate concentration was stable between 3 and 10 min of exercise but was 2- to 3-fold higher during AC (P < 0.05 versus CON). Acetylcarnitine (ACn) concentration was 6-fold higher prior to AC and remained higher during exercise. Phosphocreatine (PCr) concentration was similar prior to exercise but the decrease was 2-fold greater during AC than during CON. The time constant for the initial VO2 kinetics (phase II) was similar but the asymptote was 14% higher during AC. The slow increase in VO2 between 3 and 10 min of exercise during CON (+7.9 +/- 0.2%) was not correlated with muscle or blood lactate levels. PHE eliminated the slow increase in VO2 and reduced gross exercise efficiency during AC. It is concluded that the VO2 slow component cannot be explained by a progressive acidosis because both muscle and blood lactate levels remained stable during CON. We suggest that both the VO2 slow component during CON and the reduced gross efficiency during AC are related to impaired contractility of the working fibres and the necessity to recruit additional motor units. Despite a pronounced stockpiling of ACn during AC, initial VO2 kinetics were not affected by PHE and PCr concentration decreased to a lower plateau. The discrepancy with previous studies, where initial oxidative ATP generation appears to be limited by acetyl group availability, might relate to remaining fatiguing effects of PHE.

Hyperthermia increases exercise-induced oxidative stress.

The purpose of this investigation was to examine oxidative markers after exercise in a hyperthermic environment (35 degrees C, 70 % RH) (Hot) versus a neutral environment (25 degrees C, 40 % RH) (Con). Hyperthermia may exacerbate oxidative stress by uncoupling the mitochondrial respiratory chain or by inhibiting antioxidant defense mechanisms, but this has not been assessed in vivo. Six male subjects performed low-intensity exercise (50 % VO(2max)) on a treadmill in Hot until a core temperature of 39.5 degrees C was reached, and for an equivalent time in Con. Blood samples were drawn before and immediately after exercise and at 8 min and 15 min following exercise. Samples were analyzed for F2 isoprostanes (FIP), lipid hydroperoxides (LPO), and lactate. A 2 x 4 repeated measures ANOVA was used to test for treatment, time, and interaction effects for FIP, LPO, and lactate. Differences in VO(2) were tested with Student's t-test. Significance was set at p < 0.05. Oxygen consumption was not significantly different between Hot and Con. The pattern of change of FIP and lactate in Hot was significant versus exercise in Con. LPO was significantly elevated over time in both Hot and Con, but the pattern of change was not significantly different. Ending core temperatures and heart rates were significantly elevated in Hot versus Con. These data indicate that hyperthermia increases oxidative stress and selectively affects specific lipid markers, independent of oxygen consumption.

Lactate metabolism: a new paradigm for the third millennium.

For much of the 20th century, lactate was largely considered a dead-end waste product of glycolysis due to hypoxia, the primary cause of the O2 debt following exercise, a major cause of muscle fatigue, and a key factor in acidosis-induced tissue damage. Since the 1970s, a 'lactate revolution' has occurred. At present, we are in the midst of a lactate shuttle era; the lactate paradigm has shifted. It now appears that increased lactate production and concentration as a result of anoxia or dysoxia are often the exception rather than the rule. Lactic acidosis is being re-evaluated as a factor in muscle fatigue. Lactate is an important intermediate in the process of wound repair and regeneration. The origin of elevated [lactate] in injury and sepsis is being re-investigated. There is essentially unanimous experimental support for a cell-to-cell lactate shuttle, along with mounting evidence for astrocyte-neuron, lactate-alanine, peroxisomal and spermatogenic lactate shuttles. The bulk of the evidence suggests that lactate is an important intermediary in numerous metabolic processes, a particularly mobile fuel for aerobic metabolism, and perhaps a mediator of redox state among various compartments both within and between cells. Lactate can no longer be considered the usual suspect for metabolic 'crimes', but is instead a central player in cellular, regional and whole body metabolism. Overall, the cell-to-cell lactate shuttle has expanded far beyond its initial conception as an explanation for lactate metabolism during muscle contractions and exercise to now subsume all of the other shuttles as a grand description of the role(s) of lactate in numerous metabolic processes and pathways.

Effect of contraction frequency on the contractile and noncontractile phases of muscle venous blood flow.

The purpose of this study was to test the hypothesis that increasing muscle contraction frequency, which alters the duty cycle and metabolic rate, would increase the contribution of the contractile phase to mean venous blood flow in isolated skeletal muscle during rhythmic contractions. Canine gastrocnemius muscle (n = 5) was isolated, and 3-min stimulation periods of isometric, tetanic contractions were elicited sequentially at rates of 0.25, 0.33, and 0.5 contractions/s. The O2 uptake, tension-time integral, and mean venous blood flow increased significantly (P < 0.05) with each contraction frequency. Venous blood flow during both the contractile (106 +/- 6, 139 +/- 8, and 145 +/- 8 ml x 100 g-1 x min-1) and noncontractile phases (64 +/- 3, 78 +/- 4, and 91 +/- 5 ml x 100 g-1 x min-1) increased with contraction frequency. Although developed force and duration of the contractile phase were never significantly different for a single contraction during the three contraction frequencies, the amount of blood expelled from the muscle during an individual contraction increased significantly with contraction frequency (0.24 +/- 0.03, 0.32 +/- 0.02, and 0.36 +/- 0.03 ml x N-1 x min-1, respectively). This increased blood expulsion per contraction, coupled with the decreased time in the noncontractile phase as contraction frequency increased, resulted in the contractile phase contribution to mean venous blood flow becoming significantly greater (21 +/- 4, 30 +/- 4, and 38 +/- 6%) as contraction frequency increased. These results demonstrate that the percent contribution of the muscle contractile phase to mean venous blood flow becomes significantly greater as contraction frequency (and thereby duty cycle and metabolic rate) increases and that this is in part due to increased blood expulsion per contraction.

Effect of epinephrine on net lactate uptake by contracting skeletal muscle.

The purpose of this study was to determine the effect of epinephrine on net lactate (La(-)) uptake at constant elevated blood La(-) concentration and steady level metabolic rate (O(2) uptake) in the canine gastrocnemius-plantaris muscle in situ. Infusion of La(-)/lactic acid (pH 3.5) established a mean arterial blood La(-) concentration of ~10 mM while normal blood-gas and pH status were maintained as the gastrocnemius-plantaris was stimulated with tetanic trains at a rate of one contraction every 4 s. After steady-state control measures, epinephrine was infused for 35 min at rates that produced a high physiological concentration with (Pro; n = 6) and without (Epi; n = 6) beta-adrenergic-receptor blockade via propranolol. Net La(-) uptake values during the control conditions were not significantly different between trials (Epi: 0.756 +/- 0.043; Pro: 0.703 +/- 0.061 mmol. kg(-1). min(-1)). Steady level O(2) uptake averaged approximately 69.5 ml. kg(-1). min(-1) for both control conditions and did not significantly change over the course of the experiments in either set of trials. Epi experiments resulted in a significantly reduced net La(-) uptake (0.346 +/- 0.088 mmol. kg(-1). min(-1) after 5 min of infusion) compared with control value at all sample times measured. However, net La(-) uptake was not significantly different from control at any time during Pro (0.609 +/- 0.052 mmol. kg(-1). min(-1) after 5 min of infusion). When the change from the respective control values for net La(-) uptake was compared across time for both series of experiments, Epi resulted in a significantly greater change from control than did Pro. This study suggests that epinephrine can have a profound effect on net La(-) uptake by contracting muscle and that these effects are elicited through beta-adrenergic-receptor stimulation.

Comparison of the BOD POD with the four-compartment model in adult females.

PURPOSE: This study was designed to compare the accuracy and bias in estimates of total body density (Db) by hydrostatic weighing (HW) and the BOD POD, and percent body fat (%fat) by the BOD POD with the four-compartment model (4C model) in 42 adult females. Furthermore, the role of the aqueous and mineral fractions in the estimation of body fat by the BOD POD was examined. METHODS: Total body water was determined by isotope dilution ((2)H(2)0) and bone mineral was determined by dual-energy x-ray absorptiometry. Db and %fat were determined by the BOD POD and HW. The 4C model of Baumgartner was used as the criterion measure of body fat. RESULTS: HW Db (1.0352 g x cm(-3)) was not statistically different (P = 0.35) from BOD POD Db (1.0349 g x cm(-3)). The regression between Db by HW and the BOD POD significantly deviated from the line of identity (Db by HW = 0.90 x Db by BOD POD + 0.099; R(2) = 0.94). BOD POD %fat (28.8%) was significantly lower (P < 0.01) than %fat by the 4C model (30.6%). The regression between %fat by the 4C model and the BOD POD significantly deviated from the line of identity (%fat by 4C model = 0.88 x %fat by BOD POD + 5.41%; R(2) = 0.92). BOD POD Db and %fat showed no bias across the range of fatness. Only the aqueous fraction of the fat-free mass (FFM) had a significant correlation with the difference in %fat between the 4C model and the BOD POD. CONCLUSION: These data indicate that the BOD POD underpredicted body fat as compared with the 4C model, and the aqueous fraction of the FFM had a significant effect on estimates of %fat by the BOD POD.

Effect of a myocardial volume overload on lactate transport in skeletal muscle sarcolemmal vesicles.

This study sought to determine the effect of a myocardial volume overload (MVO) on sarcolemmal (SL) lactate (La(-)) transport and the aerobic profile of skeletal muscle. SL vesicles were obtained from female rats 10 wk after either a MVO was induced by creation of an infrarenal fistula (n = 10), or sham surgeries were performed (n = 11). Influx of (14)C-labeled L(+)-La(-) was measured at various unlabeled La(-) concentrations under zero-trans conditions. La(-) transport kinetics were determined using a Michaelis-Menten equation with an added linear component to discriminate between carrier-mediated and diffusional transport. Although heart and lung weights were significantly increased (P < 0.0001) in the MVO group, left ventricular function was only modestly altered (P < 0.05). A significant reduction in type I myosin heavy chain (MHC) in the soleus and a strong trend (P = 0.06) for a reduced type IIx MHC in the plantaris were observed in MVO rats, but no differences in citrate synthase activity or monocarboxylate transporter proteins (MCT)-1 expression were noted in any muscle. Carrier-mediated La(-) influx into SL vesicles was similar between sham and MVO (K(m) = 12 +/- 1 and 18 +/- 3 mM; apparent V(max) = 772 +/- 99 and 827 +/- 80 nmol. mg(-1). min(-1), respectively). Total influx at 100 mM was lower in MVO, and this was due to a 30% reduction in membrane diffusion. In conclusion, a 10-wk MVO did not alter MCT-mediated La(-) transport or protein expression but was associated with modest changes in myofibrillar proteins and impaired SL diffusive properties.

Role of convective O(2) delivery in determining VO(2) on-kinetics in canine muscle contracting at peak VO(2).

A previous study (Grassi B, Gladden LB, Samaja M, Stary CM, and Hogan MC, J Appl Physiol 85: 1394-1403, 1998) showed that convective O(2) delivery to muscle did not limit O(2) uptake (VO(2)) on-kinetics during transitions from rest to contractions at approximately 60% of peak VO(2). The present study aimed to determine whether this finding is also true for transitions involving contractions of higher metabolic intensities. VO(2) on-kinetics were determined in isolated canine gastrocnemius muscles in situ (n = 5) during transitions from rest to 4 min of electrically stimulated isometric tetanic contractions corresponding to the muscle peak VO(2). Two conditions were compared: 1) spontaneous adjustment of muscle blood flow (Q) (Control) and 2) pump-perfused Q, adjusted approximately 15-30 s before contractions at a constant level corresponding to the steady-state value during contractions in Control (Fast O(2) Delivery). In Fast O(2) Delivery, adenosine was infused intra-arterially. Q was measured continuously in the popliteal vein; arterial and popliteal venous O(2) contents were measured at rest and at 5- to 7-s intervals during the transition. Muscle VO(2) was determined as Q times the arteriovenous blood O(2) content difference. The time to reach 63% of the VO(2) difference between resting baseline and steady-state values during contractions was 24.9 +/- 1.6 (SE) s in Control and 18.5 +/- 1.8 s in Fast O(2) Delivery (P < 0.05). Faster VO(2) on-kinetics in Fast O(2) Delivery was associated with an approximately 30% reduction in the calculated O(2) deficit and with less muscle fatigue. During transitions involving contractions at peak VO(2), convective O(2) delivery to muscle, together with an inertia of oxidative metabolism, contributes in determining the VO(2) on-kinetics.

Muscle as a consumer of lactate.

Historically, muscle has been viewed primarily as a producer of lactate but is now considered also to be a primary consumer of lactate. Among the most important factors that regulate net lactate uptake and consumption are metabolic rate, blood flow, lactate concentration ([La]), hydrogen ion concentration ([H+]), fiber type, and exercise training. Muscles probably consume more lactate during steady state exercise or contractions because of increased lactate oxidation since enhancements in lactate transport due to acute activity are small. For optimal lactate consumption, blood flow should be adequate to maintain ideal [La] and [H+] gradients from outside to inside muscles. However, it is not clear that greater than normal blood flow will enhance lactate exchange. A widening of the [La] gradient from outside to inside muscle cells along with an increase in muscle [La] enhances both lactate utilization and sarcolemmal lactate transport. Similarly, a significant outside to inside [H+] gradient will stimulate sarcolemmal lactate influx, whereas an increased intramuscular [H+] may stimulate exogenous lactate utilization by inhibiting endogenous lactate production. Oxidative muscle fibers are metabolically suited for lactate oxidation, and they have a greater capacity for sarcolemmal lactate transport than do glycolytic muscle fibers. Endurance training improves muscle capacity for lactate utilization and increases membrane transport of lactate probably via an increase in Type I monocarboxylate transport protein (MCT1) and perhaps other MCT isoforms as well. The future challenge is to understand the regulatory roles of both lactate metabolism and membrane transport of lactate.

Differential depression of myocardial function and metabolism by lactate and H+.

The effects of both high blood H+ concentration ([H+]) and high blood lactate concentration ([lactate]) under ischemia-reperfusion conditions are receiving attention, but little is known about their effects in nonischemic hearts. Isolated rat hearts were Langendorff perfused at constant flow with media at two pH values (7.4 and 7.0) and two [lactate] (0 and 20 mM) in various sequences (n = 6/group). Coronary flow and arterial O2 content were kept constant at levels that allowed hearts to function without O2 supply limitation. We measured contractility, O2 uptake, diastolic pressure, and at the end of the protocol, tissue [lactate] and pH. Perfusion with high [lactate] raised tissue [lactate] from 5.5 +/- 0.1 to 17.5 +/- 2.6 micromol/heart (P < 0.0001), whereas decreasing the pH of the medium decreased tissue pH from 6.94 +/- 0.02 to 6.81 +/- 0.06 (P = 0.002). Heart rate was not affected by high [lactate] but was reversibly depressed by high [H+] (P = 0.004). Developed pressure declined by 20% in response to high [lactate], high [H+], and high [lactate] + high [H+] (P = 0.002). After the high-[lactate] challenge was withdrawn, pressure continued to decline. In contrast, withdrawing the high [H+] challenge allowed partial recovery. The behavior of diastolic pressure mirrored that of developed pressure. Although unaffected by high [lactate], the O2 uptake was reversibly depressed by high [H+]. This suggests higher O2 cost per contraction in the presence of high [lactate]. We conclude that for similar acute contractility depression, high [lactate] induces irreversible damage, likely at some point in the pathway of O2 utilization. In contrast, the effect of high [H+] appears reversible. These differential behaviors may have implications for heart function during heavy exercise and ischemia-reperfusion events.

Peripheral O2 diffusion does not affect V(O2)on-kinetics in isolated insitu canine muscle.

To test the hypothesis that muscle O2 uptake (V(O2)) on-kinetics is limited, at least in part, by peripheral O2 diffusion, we determined the V(O2) on-kinetics in 1) normoxia (Control); 2) hyperoxic gas breathing (Hyperoxia); and 3) hyperoxia and the administration of a drug (RSR-13, Allos Therapeutics), which right-shifts the Hb-O2 dissociation curve (Hyperoxia+RSR-13). The study was conducted in isolated canine gastrocnemius muscles (n = 5) during transitions from rest to 3 min of electrically stimulated isometric tetanic contractions (200-ms trains, 50 Hz; 1 contraction/2 s; 60-70% peak V(O2)). In all conditions, before and during contractions, muscle was pump perfused with constantly elevated blood flow (Q), at a level measured at steady state during contractions in preliminary trials with spontaneous Q x Adenosine was infused intra-arterially to prevent inordinate pressure increases with the elevated Q x Q was measured continuously, arterial and popliteal venous O2 concentrations were determined at rest and at 5- to 7-s intervals during contractions, and V(O2) was calculated as Q x arteriovenous O2 content difference. PO2 at 50% HbO2 saturation (P50) was calculated. Mean capillary PO2 (Pc(O2)) was estimated by numerical integration. P50 was higher in Hyperoxia+RSR-13 [40 +/- 1 (SE) Torr] than in Control and in Hyperoxia (31 +/- 1 Torr). After 15 s of contractions, Pc(O2) was higher in Hyperoxia (97 +/- 9 Torr) vs. Control (53 +/- 3 Torr) and in Hyperoxia+RSR-13 (197 +/- 39 Torr) vs. Hyperoxia. The time to reach 63% of the difference between baseline and steady-state V(O2) during contractions was 24.7 +/- 2.7 s in Control, 26.3 +/- 0.8 s in Hyperoxia, and 24.7 +/- 1.1 s in Hyperoxia+RSR-13 (not significant). Enhancement of peripheral O2 diffusion (obtained by increased PcO2 at constant O2 delivery) during the rest-to-contraction (60-70% of peak V(O2)) transition did not affect muscle V(O2) on- kinetics.

Faster adjustment of O2 delivery does not affect V(O2) on-kinetics in isolated in situ canine muscle.

The mechanism(s) limiting muscle O2 uptake (VO2) kinetics was investigated in isolated canine gastrocnemius muscles (n = 7) during transitions from rest to 3 min of electrically stimulated isometric tetanic contractions (200-ms trains, 50 Hz; 1 contraction/2 s; 60-70% of peak V(O2)). Two conditions were mainly compared: 1) spontaneous adjustment of blood flow (Q) [control, spontaneous Q (C Spont)]; and 2) pump-perfused Q, adjusted approximately 15 s before contractions at a constant level corresponding to the steady-state value during contractions in C Spont [faster adjustment of O2 delivery (Fast O2 Delivery)]. During Fast O2 Delivery, 1-2 ml/min of 10(-2) M adenosine were infused intra-arterially to prevent inordinate pressure increases with the elevated Q. The purpose of the study was to determine whether a faster adjustment of O2 delivery would affect V(O2) kinetics. Q was measured continuously; arterial (Ca(O2)) and popliteal venous (Cv(O2)) O2 contents were determined at rest and at 5- to 7-s intervals during contractions; O2 delivery was calculated as Q x Ca(O2), and V(O2) was calculated as Q x arteriovenous O2 content difference. Times to reach 63% of the difference between baseline and steady-state VO2 during contractions were 23.8 +/- 2.0 (SE) s in C Spont and 21.8 +/- 0.9 s in Fast O2 Delivery (not significant). In the present experimental model, elimination of any delay in O2 delivery during the rest-to-contraction transition did not affect muscle V(O2) kinetics, which suggests that this kinetics was mainly set by an intrinsic inertia of oxidative metabolism.

Lactate distribution in the blood during steady-state exercise.

PURPOSE: The purpose of this investigation was to examine the plasma to red blood cell (RBC) lactate concentration ([La]) gradient and RBC:plasma [La] ratio during 30 min of steady-state cycle ergometer exercise at work rates below lactate threshold ( LT. Blood samples were taken from a heated forearm vein, immediately cooled to 4 degrees C in a dry-ice ethanol slurry, and centrifuged at 4 degrees C to separate plasma and RBCs. RESULTS: During >LT, plasma [La] rose to 8.8+/-1.1 mM after 10 min and remained above 6 mM. RBC [La] (4.9+/-0.7 mM) was significantly lower than plasma [La] at 10 min and remained lower throughout exercise. As a result, there was a sizable [La] gradient (approximately 3.5 mM) from plasma to RBC during most of >LT. In LT, the ratio of RBC [La]:plasma [La] was the same for both (0.58+/-0.02) and not significantly different from rest. CONCLUSIONS: These results refuted our hypothesis that the RBC:plasma [La] ratio would decrease at the onset of >LT exercise because of muscle lactate release exceeding the ability of RBCs to take up the lactate. Instead, there appears to be an equilibrium between plasma [La] and RBC [La] in arterialized venous blood from a resting muscle group as evidenced by the constant RBC [La]:plasma [La] ratio.