Effect of flow on O2 consumption during progressive hypoxemia

Rabbit hindlimb preparations perfused with blood from donor rabbits were used to determine whether O2 consumption (VO2) during hypoxemia is limited by total O2 transport (TO2) or by capillary O2 driving pressure, as reflected by the venous PO2 (PVO2). The preparations were randomized into two groups: low flow (LF) and high flow (HF), perfused at 18 and 32 ml.min-1.kg of preparation wt-1, respectively. After a 1-h base-line period with arterial PO2 (PaO2) greater than 100 Torr, both groups were exposed to progressive decrements in PaO2 to less than 10 Torr. Sequential sets of arterial and venous blood gases were obtained, and VO2, TO2, and O2 extraction ratio (ERO2) were calculated. A plot of PVO2 vs. TO2 showed higher levels of PVO2 (P less than 0.05) in LF than HF, when compared at similar levels of TO2. Therefore the experimental protocol allowed the comparison of the separate effects of TO2 or PVO2 on VO2. Plotting VO2 as a function of TO2 revealed two distinct curves (P less than 0.05), with LF having a greater VO2 than HF at a given TO2. Conversely, a plot of VO2 as a function of PVO2 did not show a difference between the groups. The ERO2 of LF was greater than HF when compared at similar levels of TO2 (P less than 0.05). We conclude from these data that during progressive hypoxemia VO2 appears to be primarily limited by factors that determine capillary O2 diffusion. This conclusion supports the Kroghian theory of capillary O2 exchange.     

Skeletal muscle PO2 during hypoxemia and isovolemic anemia

We subjected anesthetized mechanically ventilated rabbits (n = 6) to sequential exchanges of blood for a 6% dextran solution and compared their responses with those obtained in a previous study on progressive hypoxemia (n = 7). Right atrial PO2 (PVO2)RA and hindlimb PO2 (PVO2)limb, measured at the level of the iliac bifurcation, were compared with tissue PO2 (PtiO2) histograms obtained with an array of surface microelectrodes placed over the biceps femoris muscle. Systemic O2 consumption (VO2) was measured with the expired gas method. Cardiac output and systemic O2 transport (TO2) were calculated. Six exchanges of blood for dextran produced decreases in hemoglobin from 10.8 +/- 0.4 to 2.7 +/- 0.2 g/dl (P less than 0.001). Critical TO2 (TO2crit), defined as the level of TO2 associated with initial decreases in control VO2, was similar for anemia and hypoxemia (40.5 +/- 5.6 and 40.1 +/- 5.3 ml.min-1.kg-1, respectively). At any given TO2 other than control TO2, the levels of (PVO2)RA and (PVO2)limb were greater in anemia than in hypoxemia (P less than 0.01), but the mean and the distribution of the PtiO2 histograms were similar in both conditions. Mean PtiO2 was significantly less than (PVO2)RA or (PVO2)limb, except for those values obtained during the control period. These results confirm our previous finding that PVO2 is not an accurate index of PtiO2 under conditions of tissue hypoxia. Furthermore, similar PtiO2 levels during anemia and hypoxemia suggest that VO2 is limited by decreases in O2 diffusion from the capillaries to the cells.     

Effect of respiratory alkalosis on skeletal muscle metabolism in the dog

These experiments were conducted to determine whether changes in skeletal muscle metabolism contribute to the previously reported increase in whole-body O2 uptake (VO2) during respiratory alkalosis. The hind-limb and gastrocnemius-plantaris preparations in anesthetized and paralyzed dogs were used. VO2 of the hindlimb and gastrocnemius muscle was calculated from measurements of venous blood flow and arterial and venous O2 concentrations (Van Slyke analysis). Whole-body VO2 was measured by the open-circuit method. Minute ventilation (hence blood gases and pH) was controlled by a mechanical respirator. Whole-body, hind-limb, and gastrocnemius muscle VO2 increased 14, 19, and 20%, respectively, during alkalosis (P less than 0.05). In all experiments, arterial lactate concentration increased significantly (P less than 0.05) during alkalosis. A positive venoarterial lactate difference across muscle during alkalosis indicated that skeletal muscle is a source of the elevated blood lactate. We concluded that VO2 of resting skeletal muscle is increased during states of respiratory alkalosis and that this increase can account for much of the increase in whole-body VO2.     

Effect of endotoxin on systemic and skeletal muscle O2 extraction

Patients with the adult respiratory distress syndrome (ARDS) show a pathological dependence of O2 consumption (VO2) on O2 delivery (QO2, blood flow X arterial O2 content). In these patients, a defect in tissues' ability to extract O2 from blood can leave tissue O2 needs unmet, even at a normal QO2. Endotoxin administration produces a similar state in dogs, and we used this model to study mechanisms that may contribute to human pathology. We measured systemic and hindlimb VO2 and QO2 while reducing cardiac output by blood withdrawal. At the onset of supply dependence, the systemic QO2 was 11.4 +/- 2.7 ml.kg-1.min-1 in the endotoxin group vs. 8.0 +/- 0.7 in controls (P less than 0.05). At this point, the endotoxin-treated animals extracted only 61 +/- 11% of the arterial O2, whereas control animals extracted 70 +/- 7% (P less than 0.05). Systemic VO2 rose by 15% after endotoxin (P less than 0.05) but did not change in controls. Despite this poorer systemic ability to extract O2 by the endotoxin-treated dogs, isolated hindlimb O2 extraction at the onset of supply dependence was the same in endotoxin-treated and control dogs. At normal levels of QO2, hindlimb VO2 in endotoxin-treated dogs was 23% higher than in controls (P less than 0.05). Fractional blood flow to skeletal muscle did not differ between control and endotoxin-treated dogs. Thus skeletal muscle was not overperfused in endotoxemia and did not contribute to a systemic extraction defect by stealing blood flow from other tissues. Skeletal muscle in endotoxin-treated dogs demonstrated an increase in VO2 but no defect in O2 extraction, differing in both respects from the intestine.     

Active muscle and whole body lactate kinetics after endurance training in men.

We evaluated the hypotheses that endurance training decreases arterial lactate concentration ([lactate](a)) during continuous exercise by decreasing net lactate release () and appearance rates (R(a)) and increasing metabolic clearance rate (MCR). Measurements were made at two intensities before [45 and 65% peak O(2) consumption (VO(2 peak))] and after training [65% pretraining VO(2 peak), same absolute workload (ABT), and 65% posttraining VO(2 peak), same relative intensity (RLT)]. Nine men (27.4 +/- 2.0 yr) trained for 9 wk on a cycle ergometer, 5 times/wk at 75% VO(2 peak). Compared with the 65% VO(2 peak) pretraining condition (4.75 +/- 0.4 mM), [lactate](a) decreased at ABT (41%) and RLT (21%) (P < 0.05). decreased at ABT but not at RLT. Leg lactate uptake and oxidation were unchanged at ABT but increased at RLT. MCR was unchanged at ABT but increased at RLT. We conclude that 1) active skeletal muscle is not solely responsible for elevated [lactate](a); and 2) training increases leg lactate clearance, decreases whole body and leg lactate production at a given moderate-intensity power output, and increases both whole body and leg lactate clearance at a high relative power output.     

Hydrogen ion concentration and oxygen uptake in an isolated canine hindlimb.

Oxygen utilization (VO2) and lactate production by an isolated perfused canine hindlimb was evaluated at various hydrogen ion concentrations. A membrane lung perfusion system was established such that blood flow and temperature could be fixed at normal levels. Oxygen, nitrogen, and carbon dioxide (CO2) gas flows to the membrane lung were independently regulated to provide a fixed arterial oxygen content (CaO2). By changing CO2 flow, the pH of the arterial blood was varied between 6.9 and 7.6 at 10-min intervals. The mean O2 delivery (CaO2 X blood flow) was between 16.3 ML O2/min and 20.5 ml O2/min. Standard error of the mean in each dog, however, was less than 0.4 ml O2/min. VO2 was linearly related to the pH of the perfusing blood: VO2% = 100.1 pH - 643 (r = 0.866). Oxygen consumption was inversely related to PCO2: VO2% = -0.62 PCO2 + 124, but the correlation was less good (r = 0.729). Lactate production was linearly related to the pH of the perfusing blood (above a pH of 7.4): lactate produced = 22.5 pH - 162.5 (r = 0.75). At a pH below 7.4, lactate was not produced. Oxygen consumption of skeletal muscle appears critically dependent on extracellular fluid pH. A change in pH of 0.1 alters VO2 almost exactly 10%. Alkalosis is a potent stimulus to lactic acid production by skeletal muscle.     

Hindlimb vascular responses to sympathetic augmentation during acute anemia

The effect of increased sympathetic activity on skeletal muscle blood flow during acute anemic hypoxia was studied in 16 anesthetized dogs. Sympathetic activity was altered by clamping the carotid arteries bilaterally below the carotid sinus. One group (n = 8) was beta blocked by administration of propranolol (1 mg/kg); a second group (n = 8) was untreated. Venous outflow from the left hindlimb was isolated for measurement of blood flow and O2 uptake (VO2). After a 20-min control period, both carotid arteries were clamped (CC) for 20 min followed by a 20-min recovery period. The sequence was repeated after hematocrit was lowered to about 15% by dextran exchange for blood. Prior to anemia, CC did not alter cardiac output or limb blood flow in either group. After induction of anemia, hindlimb resistance was higher with CC in the beta block than in the no block group. Both limb blood flow and VO2 fell in the beta-block group with CC during anemia. Beta block also prevented the additive increases in whole body VO2 seen with CC and induction of anemia. The data showed that the increased vasoconstrictor tone that was obtained with beta block during anemia was successful in redistributing the lower viscosity blood away from resting skeletal muscle, even to the point that muscle VO2 was decreased.     

Skeletal muscle O2 consumption and energy metabolism during hypoxemia

We determined the relationship of O2 transport (TO2) to O2 consumption (VO2) and to changes in cellular bioenergetics in an isolated blood-perfused rabbit hindlimb preparation (n = 8) during hypoxemia. The preparations were subjected to reductions in TO2 by progressively decreasing partial pressure of arterial O2 (PaO2). At each level of PaO2 we obtained simultaneous measures of arterial and venous blood gases, venous lactate concentration, and changes in the relative concentrations of inorganic phosphate, phosphocreatine, and ATP measured with 31P magnetic resonance spectroscopy. The ratio of the change in vascular resistance (R) to the corresponding decrease in TO2 was taken as an index of vascular autoregulation with hypoxemia. Linear and logarithmic functions were fitted by least squares to the TO2-VO2 data from each experiment. TO2-VO2 relationships were characterized as O2 conforming (linear function, n = 4) or O2 regulating (logarithmic function, n = 4), depending on the goodness of fit. Those preparations showing an O2-conforming pattern had higher control VO2 (2.42 +/- 0.14 vs. 1.66 +/- 0.19 ml.min-1.kg-1; P less than 0.05) and a lesser degree of vascular autoregulation (0.07 +/- 0.03 vs. 0.21 +/- 0.02; P less than 0.01) than the O2-regulating group. Decreases in VO2 were always accompanied by increases in inorganic phosphate and lactate and decreases in phosphocreatine, indicating O2 supply limitation and anaerobic ATP production. There was no evidence of cellular adaptation to hypoxia by decreasing energy needs or of VO2 limitation by the depletion of adenine nucleotides.     

Effects of high-intensity sprint training on skeletal muscle blood flow in rats.

The regional blood flow response (via radioactive microspheres) was determined for female rats after 6 wk of high-intensity sprint training (HIST) or limited cage activity as the animals exercised at work loads that would elicit maximal O2 uptake. Blood flow to the different organs of the abdominal region was greatly reduced during maximal exercise conditions, and the magnitude of the reduction appeared to be similar for both the HIST group of rats and their sedentary (SED) control counterparts. Of the 20 different hindlimb muscles examined in the present study, blood flow to the soleus, plantaris, gastrocnemius, flexor hallicus longus, vastus lateralis, rectus femoris, biceps femoris, and adductor magnus and brevis muscles was significantly greater (P less than 0.05) in the HIST rats during maximal exercise conditions than in the SED control rats. Correspondingly, blood flow to the total hindlimb during maximal exercise was also significantly greater in the HIST rats than in the SED control rats [240 +/- 18 vs. 192 +/- 15 (SE) ml.min-1.100 g-1]. These results support the contention that the increase in maximal cardiac output that is produced by HIST in the rat is primarily directed toward the working skeletal muscle and not toward the organs found in the abdominal region. We conclude from these experiments that HIST will produce significant adaptations in central cardiac function and skeletal muscle blood flow in the rat.     

Bioenergetics of rabbit skeletal muscle during hypoxemia and ischemia

A blood-perfused rabbit hindlimb preparation was exposed to total ischemia (n = 4) or to severe hypoxemia (n = 4) where arterial PO2 was 5 +/- 2 (SE) Torr. O2 consumption (VO2), O2 transport (TO2), venous PO2 (PVO2), venous lactate concentration, and venous glucose concentration were measured. The relative concentration of ATP, phosphocreatine (PCr), inorganic phosphate (Pi), and intracellular pH (pHi) were monitored with 31P magnetic resonance spectroscopy. PCr/Pi decreased with the onset of ischemia or hypoxemia. The preparation was reoxygenated and allowed to recover for 30 min once PCr/Pi was less than 1.0. The periods of hypoxemia and ischemia lasted 56.0 +/- 10.0 and 63.8 +/- 2.5 min, respectively (NS). During ischemia PCr decreased and Pi increased compared with control (P less than 0.05) but returned to control with reperfusion. With hypoxemia PCr also decreased and Pi increased with respect to control (P less than 0.01) but did not recover with reoxygenation. VO2 and PVO2 in both groups returned to control during recovery. ATP did not change with ischemia but decreased with hypoxemia (P less than 0.05). Venous lactate concentration did not change with ischemia but increased with hypoxemia (P less than 0.05) and continued to rise during recovery. During recovery pHi decreased in the hypoxemic group (P less than 0.05) but not in the ischemic group. These data show that, under the conditions tested, rabbit skeletal muscle does not resynthesize PCr after a severe hypoxemic episode. Furthermore it appears that VO2 and PVO2 fail to portray the true state of cellular bioenergetics after a severe hypotemic insult.     

Lactate production under fully aerobic conditions: the lactate shuttle during rest and exercise

O2 insufficiency and other factors increase the rate of lactate production. Significant quantities of lactate are produced under postabsorptive as well as postprandial conditions in resting individuals. In humans during postabsorptive rest, 25-50% of the total carbohydrate combusted appears to pass through the lactate pool. During sustained submaximal (in terms of VO2max) exercise, the rates of lactate production (Ri) and oxidation (Rox) are greatly elevated as compared to rest. However, lactate production and oxidation increase relatively less than O2 consumption during moderate-intensity exercise. Because the lactate production index (RiI = Ri/VO2) decreases during submaximal, moderate-intensity exercise compared to rest, it is concluded that skeletal muscle and other sites of lactate production are effectively oxygenated. Alterations in the levels of circulating catecholamines can affect levels and turnover rates of glucose and lactate. In pure red dog gracilis muscle in situ and in the healthy and myocardium in vivo, contraction results in glycolysis and lactate production. This production of lactate occurs despite an apparent abundance of O2. Similarly, glucose catabolism in the human brain results in lactate production. The formation of lactate under fully aerobic conditions of rest and exercise represents an important mechanism by which different tissues share a carbon source (lactate) for oxidation and other processes such as gluconeogenesis. This mechanism has been termed the lactate shuttle.     

Acute vs. chronic effects of elevated hemoglobin O(2) affinity on O(2) transport in maximal exercise.

These studies were conducted to compare the effects on systemic O(2) transport of chronically vs. acutely increased Hb O(2) affinity. O(2) transport during maximal normoxic and hypoxic [inspired PO(2) (PI(O(2))) = 70 and 55 Torr, respectively] exercise was studied in rats with Hb O(2) affinity that was increased chronically by sodium cyanate (group 1) or acutely by transfusion with blood obtained from cyanate-treated rats (group 2). Group 3 consisted of normal rats. Hb O(2) half-saturation pressure (P(50); Torr) during maximal exercise was approximately 26 in groups 1 and 2 and approximately 46 in group 3. In normoxia, maximal blood O(2) convection (TO(2 max) = cardiac output x arterial blood O(2) content) was similar in all groups, whereas in hypoxia TO(2 max) was significantly higher in groups 1 and 2 than in group 3. Tissue O(2) extraction (arteriovenous O(2) content/arterial O(2) content) was lowest in group 1, intermediate in group 2, and highest in group 3 (P < 0.05) at all exercise PI(O(2)) values. In normoxia, maximal O(2) utilization (VO(2 max)) paralleled O(2) extraction ratio and was lowest in group 1, intermediate in group 2, and highest in group 3 (P < 0.05). In hypoxia, the lower O(2) extraction ratio values of groups 1 and 2 were offset by their higher TO(2 max); accordingly, their differences in VO(2 max) from group 3 were attenuated or reversed. Tissue O(2) transfer capacity (VO(2 max)/mixed venous PO(2)) was lowest in group 1 and comparable in groups 2 and 3. We conclude that lowering Hb P(50) has opposing effects on TO(2 max) and O(2) extraction ratio, with the relative magnitude of these changes, which varies with PI(O(2)), determining VO(2 max). Although the lower O(2) extraction ratio of groups 2 vs. 3 suggests a decrease in tissue PO(2) diffusion gradient secondary to the low P(50), the lower O(2) extraction ratio of groups 1 vs. 2 suggests additional negative effects of sodium cyanate and/or chronically low Hb P(50) on tissue O(2) transfer.     

Oxygen transport during exercise in large mammals. I. Adaptive variation in oxygen demand

This study investigated mechanisms used by horses and steers to increase O2 uptake and delivery (VO2) from resting to maximal rates and identified the mechanisms that enable horses to achieve higher maximal rates of O2 consumption (VO2max) than steers. VO2 and circulatory variables were measured while Standardbred trotting horses and steers (450-kg body mass) stood quietly and ran on a treadmill at speeds up to those eliciting VO2max. As VO2 increased in both species, heart rate and circulating hemoglobin (Hb) concentration increased, thereby increasing O2 delivery by the circulation, while cardiac stroke volume remained unchanged. At VO2max arterial PCO2 increased from its resting value in horses but was unchanged in steers, and arterial PO2 decreased in both species. Although the horses hypoventilated and were hypoxemic at VO2max, no significant decrease in arterial Hb saturation occurred. VO2max of the horses was 2.6 times higher than that of the steers and was associated with a 100% larger cardiac output, 100% larger stroke volume, and 40% higher Hb concentration, whereas heart rates at VO2max were identical in the two species. The higher cardiac output of the horses at VO2max resulted from a 1.2-fold higher mean arterial pressure and 1.6-fold lower peripheral tissue resistance (associated with a larger skeletal muscle capillary bed). Both the magnitude of the difference in VO2max between horses and steers and the mechanisms used to achieve it are the same as observed in smaller pairs of mammalian species with large variation in aerobic capacity.     

Peripheral vascular responses to hypoxic hypoxia after aortic denervation

We wished to see whether aortic chemoreceptors and other vagal afferent traffic played an essential role in the circulatory adjustments to hypoxic hypoxia. Aortic chemoreceptors were denervated (AD) in one group (n = 6) of anesthetized dogs, bilateral cervical vagotomy (V) was done on a second group (n = 6), and a third group (n = 6) was sham-operated to serve as a control. Venous outflow from the left hindlimb was isolated. After a 20-min control period of ventilation with room air, the animals were ventilated for 60 min with 9% of O2 in N2. Arterial, mixed venous, and hindlimb venous blood samples were taken every 20 min. The cardiac output response to hypoxic hypoxia was attenuated at 40 and 60 min in both the AD and V groups (p less than 0.05). Hindlimb blood flow increased equally in all three groups during hypoxia. The pressor response at the onset of hypoxia (20 min) was abolished in the AD and V groups, but mean arterial pressure fell to similar levels in all three groups by 60 min of hypoxia. We concluded that reflex aortic chemoreceptor stimulation during hypoxia augmented cardiac output mostly by effects on the venous side of the circulation but played no role in skeletal muscle vascular responses to hypoxic hypoxia.     

Dynamic exercise training in foxhounds. I. Oxygen consumption and hemodynamic responses

Ten foxhounds were studied during maximal and submaximal exercise on a motor-driven treadmill before and after 8-12 wk of training. Training consisted of working at 80% of maximal heart rate 1 h/day, 5 days/wk. Maximal O2 consumption (VO2max) increased 28% from 113.7 +/- 5.5 to 146.1 +/- 5.4 ml O2 X min-1 X kg-1, pre- to posttraining. This increase in VO2max was due primarily to a 27% increase in maximal cardiac output, since maximal arteriovenous O2 difference increased only 4% above pretraining values. Mean arterial pressure during maximal exercise did not change from pre- to posttraining, with the result that calculated systemic vascular resistance (SVR) decreased 20%. There were no training-induced changes in O2 consumption, cardiac output, arteriovenous O2 difference, mean arterial pressure, or SVR at any level of submaximal exercise. However, if post- and pretraining values are compared, heart rate was lower and stroke volume was greater at any level of submaximal exercise. Venous lactate concentrations during a given level of submaximal exercise were significantly lower during posttraining compared with pretraining, but venous lactate concentrations during maximal exercise did not change as a result of exercise training. These results indicate that a program of endurance training will produce a significant increase in VO2max in the foxhound. This increase in VO2max is similar to that reported previously for humans and rats but is derived primarily from central (stroke volume) changes rather than a combination of central and peripheral (O2 extraction) changes.     

O2 delivery at VO2max and oxidative capacity in muscles of standardbred horses.

The purpose of this study was to describe the relationships between 16 physiological, biochemical, and morphological variables presumed to relate to the oxidative capacity in quadriceps muscles or muscle parts in Standardbred horses. The variables included O2 delivery (blood flow) and mean capillary transit time (MTT) during treadmill locomotion at whole animal maximal O2 consumption (VO2max, 134 +/- 2 ml.min-1 x kg-1), capillary density and capillary-to-fiber ratio, myoglobin concentration, oxidative enzyme activities, glycolytic enzyme activities, fiber type populations, and fiber size. These components of muscle metabolic capacity were found to be interrelated to varying degrees using correlation matrix analysis, with lactate dehydrogenase activity showing the most significant correlations (n = 14) with other variables. Most of the "oxidative" variables occurred in the highest quantities in the deepest muscle of the group (vastus intermedius) and in the deepest parts of the other quadriceps muscles where the highest proportions of type I fibers were localized. The highest blood flow measured with microspheres in the muscle group during exercise was in vastus intermedius muscle (145 ml.min-1 x 100 g-1), and the lowest was in the superficial part of rectus femoris muscle (32 ml.min-1 x 100 g-1). Average muscle blood flow during exercise at whole animal VO2max was 116 ml.min-1 x 100 g-1. Because skeletal muscle comprised 43% of total body mass (453 +/- 34 kg), total muscle blood flow was estimated at 226 l/min, which was approximately 78% of total cardiac output (288 l/min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Muscle respiratory capacity and VO2 max in identically trained young and old rats

Old rats have a decreased hindlimb muscle respiratory capacity and whole-body maximal O2 consumption (VO2 max). The decline in spontaneous physical activity in old rats might contribute to these age-related changes. The magnitude of the age-related decline is not uniform in all skeletal muscle respiratory enzymes, and the decrease in palmitate oxidation is particularly great. This study was designed to determine if young and old rats subjected to the same exercise-training protocol would attain similar values for VO2 max and several markers of muscle respiratory capacity. Four- and 18-mo-old Fischer 344 rats underwent an identical 6-mo program of treadmill running. After training, both age groups had increased VO2 max above sedentary age-matched controls. However, the old trained rats had a lower VO2 max than identically trained young rats. In contrast to VO2 max, the two trained groups attained similar values for gastrocnemius citrate synthase, cytochrome oxidase, 3-hydroxyacyl-CoA dehydrogenase, palmitate oxidation, and total carnitine concentration. Thus, when the young and old rats performed an identical exercise protocol within the capacity of the old animals, differences in skeletal muscle respiratory capacity were eliminated. The dissimilarity in VO2 max between the identically trained groups was apparently caused by age-related differences in factors other than muscle respiratory capacity.     

Limitation of maximal O2 uptake and performance by acute hypoxia in dog muscle in situ

The factors that determine maximal O2 uptake (VO2max) and muscle performance during severe, acute hypoxemia were studied in isolated, in situ dog gastrocnemius muscle. Our hypothesis that VO2max is limited by O2 diffusion in muscle predicts that decreases in VO2max, caused by hypoxemia, will be accompanied by proportional decreases in muscle effluent venous PO2 (PvO2). By altering the fraction of inspired O2, four levels of arterial PO2 (PaO2) [21 +/- 2, 28 +/- 1, 44 +/- 1, and 80 +/- 2 (SE) Torr] were induced in each of eight dogs. Muscle arterial and venous circulation was isolated and arterial pressure held constant by pump perfusion. Each muscle worked maximally (3 min at 5-6 Hz, isometric twitches) at each PaO2. Arterial and venous samples were taken to measure lactate, [H+], PO2, PCO2, and muscle VO2. Muscle biopsies were taken to measure [H+] (homogenate method) and lactate. VO2max decreased with PaO2 and was linearly (R = 0.99) related to both PVO2 and O2 delivery. As PaO2 fell, fatigue increased while muscle lactate and [H+] increased. Lactate release from the muscle did not change with PaO2. This suggests a barrier to lactate efflux from muscle and a possible cause of the greater fatigue seen in hypoxemia. The gas exchange data are consistent with the hypothesis that VO2max is limited by peripheral tissue diffusion of O2.     

Effect of endurance training and chronic isoproterenol treatment on skeletal muscle sensitivity to norepinephrine

The purpose of this study was to determine the influence of metabolic stresses, such as endurance training and chronic isoproterenol treatment, on skeletal muscle sensitivity to norepinephrine. Using an isolated perfused rat hindlimb preparation, dose-response curves for skeletal muscle oxygen consumption (VO2) and vascular resistance were obtained with control, endurance trained, and isoproterenol treated rats. No significant difference was found between control and experimental groups for non-stimulated VO2. In response to NE infusion, trained rats showed a significantly greater increase in VO2 compared to control rats while the response of the isoproterenol treated rats was of the same magnitude as the one for their respective control rats. At the highest dose of NE infused, the vasopressor response was significantly lower in trained rats compared to control rats. At none of the doses was there a significant difference in the vasopressor response between control and isoproterenol treated rats. These results suggest that repeated exposures to high levels of catecholamines, as produced during endurance training, leads to an increased sensitivity of skeletal muscle to the effect of norepinephrine.     

Physiological and biochemical correlates of increased work in trained iron-deficient rats

We investigated physiological and biochemical factors associated with the improved work capacity of trained iron-deficient rats. Female 21-day-old rats were assigned to one of four groups, two dietary groups (50 and 6 ppm dietary iron) subdivided into two levels of activity (sedentary and treadmill trained). Iron deficiency decreased hemoglobin (61%), maximal O2 uptake. (VO2max) (40%), skeletal muscle mitochondrial oxidase activities (59-90%), and running endurance (94%). In contrast, activities of tricarboxylic acid (TCA) cycle enzymes in skeletal muscle were largely unaffected. Four weeks of mild training in iron-deficient rats resulted in improved blood lactate homeostasis during exercise and increased VO2max (15%), TCA cycle enzymes of skeletal muscle (27-58%) and heart (29%), and liver NADH oxidase (34%) but did not affect any of these parameters in the iron-sufficient animals. In iron-deficient rats training affected neither the blood hemoglobin level nor any measured iron-dependent enzyme pathway of skeletal muscle but substantially increased endurance (230%). We conclude that the training-induced increase in endurance in iron-deficient rats may be related to cardiovascular improvements, elevations in liver oxidative capacity, and increases in the activities of oxidative enzymes that do not contain iron in skeletal and cardiac muscle.