Effects of hyperoxic gas mixtures on energy metabolism during prolonged work.

These experiments were designed to study selected respiratory and metabolic responses to exercise in hyperoxia. Four subjects were examined during 30-min bicycle ergometer rides at both 40% and 80% of their aerobic maximum. The VO2 was significantly increased at both work levels breathing 60% O2 versus 21% O2, while VCO2 showed no significant change during the 40% exercise tests but was significantly decreased during the 80% intensity rides. The average increase in the volume of O2 taken up during 30 min of hyperoxic exercise, compared with normoxia, was 3.3 liters at the 40% exercise level and 5.6 liters at the 80% level. Neither the magnitude of the O2 nor the CO2 storage calculated for the exercise bouts could explain these increases. Steady-state criteria for the gas stores were established by the stable values of PETCO2, VO2, VCO2, and VI from minute 6 through 30 at both work levels. R values decreased during the hyperoxic tests suggesting the possibility of a shift toward increased fatty acid metabolism.     

Hyperoxia enhances metaboreflex sensitivity during static exercise in humans

Peripheral chemoreflex inhibition with hyperoxia decreases sympathetic nerve traffic to muscle circulation [muscle sympathetic nerve activity (MSNA)]. Hyperoxia also decreases lactate production during exercise. However, hyperoxia markedly increases the activation of sensory endings in skeletal muscle in animal studies. We tested the hypothesis that hyperoxia increases the MSNA and mean blood pressure (MBP) responses to isometric exercise. The effects of breathing 21% and 100% oxygen at rest and during isometric handgrip at 30% of maximal voluntary contraction on MSNA, heart rate (HR), MBP, blood lactate (BL), and arterial O2 saturation (SaO2) were determined in 12 healthy men. The isometric handgrips were followed by 3 min of postexercise circulatory arrest (PE-CA) to allow metaboreflex activation in the absence of other reflex mechanisms. Hyperoxia lowered resting MSNA, HR, MBP, and BL but increased Sa(O2) compared with normoxia (all P < 0.05). MSNA and MBP increased more when exercise was performed in hyperoxia than in normoxia (MSNA: hyperoxic exercise, 255 +/- 100% vs. normoxic exercise, 211 +/- 80%, P = 0.04; and MBP: hyperoxic exercise, 33 +/- 9 mmHg vs. normoxic exercise, 26 +/- 10 mmHg, P = 0.03). During PE-CA, MSNA and MBP remained elevated (both P < 0.05) and to a larger extent during hyperoxia than normoxia (P < 0.05). Hyperoxia enhances the sympathetic and blood pressure (BP) reactivity to metaboreflex activation. This is due to an increase in metaboreflex sensitivity by hyperoxia that overrules the sympathoinhibitory and BP lowering effects of chemoreflex inhibition. This occurs despite a reduced lactic acid production.     

Energy expenditure during simulated rowing

Metabolic function was measured by open-circuit spirometry for 310 competitive oarsmen during and following a 6-min maximal rowing ergometer exercise. Aerobic and anaerobic energy contributions to exercise were estimated by calculating exercise O2 cost and O2 debt.O2 debt was measured for 30 min of recovery using oxygen consumption (Vo2) during light rowing as the base line. Venous blood lactates were analyzed at rest and at 5 and 30 min of recovery. Maximal ventilation volumes ranged from 175 to 22l 1/min while Vo2 max values averaged 5,950 ml/min and 67.6 ml/kg min. Maximal venous blood lactates ranged from 126 to 240 mg/100 ml. Average O2 debt equaled 13.4 liters. The total energy cost for simulated rowing was calculated at 221.5 kcal assuming 5 kcal/l O2 with aerobic metabolism contributing 70% to the total energy released and anaerobiosis providing the remaining 30%. Vo2 values for each minute of exercise reflect a severe steady state since oarsmen work at 96-98% of maximal aerobic capacity. O2 debt and lactate measurements attest to the severity of exercise and dominance of anaerobic metabolism during early stages of work.     

Hyperbaric hyperoxia reduces exercising forearm blood flow in humans

Hypoxia during exercise augments blood flow in active muscles to maintain the delivery of O(2) at normoxic levels. However, the impact of hyperoxia on skeletal muscle blood flow during exercise is not completely understood. Therefore, we tested the hypothesis that the hyperemic response to forearm exercise during hyperbaric hyperoxia would be blunted compared with exercise during normoxia. Seven subjects (6 men/1 woman; 25 ± 1 yr) performed forearm exercise (20% of maximum) under normoxic and hyperoxic conditions. Forearm blood flow (FBF; in ml/min) was measured using Doppler ultrasound. Forearm vascular conductance (FVC; in ml·min(-1)·100 mmHg(-1)) was calculated from FBF and blood pressure (in mmHg; brachial arterial catheter). Studies were performed in a hyperbaric chamber with the subjects supine at 1 atmospheres absolute (ATA) (sea level) while breathing normoxic gas [21% O(2), 1 ATA; inspired Po(2) (Pi(O(2))) ≈ 150 mmHg] and at 2.82 ATA while breathing hyperbaric normoxic (7.4% O(2), 2.82 ATA, Pi(O(2)) ≈ 150 mmHg) and hyperoxic (100% O(2), 2.82 ATA, Pi(O(2)) ≈ 2,100 mmHg) gas. Resting FBF and FVC were less during hyperbaric hyperoxia compared with hyperbaric normoxia (P < 0.05). The change in FBF and FVC (Δ from rest) during exercise under normoxia (204 ± 29 ml/min and 229 ± 37 ml·min(-1)·100 mmHg(-1), respectively) and hyperbaric normoxia (203 ± 28 ml/min and 217 ± 35 ml·min(-1)·100 mmHg(-1), respectively) did not differ (P = 0.66-0.99). However, the ΔFBF (166 ± 21 ml/min) and ΔFVC (163 ± 23 ml·min(-1)·100 mmHg(-1)) during hyperbaric hyperoxia were substantially attenuated compared with other conditions (P < 0.01). Our data suggest that exercise hyperemia in skeletal muscle is highly dependent on oxygen availability during hyperoxia.     

Muscle and blood ammonia and lactate responses to prolonged exercise with hyperoxia

Investigations using nonsteady-state and fatiguing exercise protocols have demonstrated a strong relationship between ammonia and lactate metabolism and have suggested a cause and effect relationship between these two variables. We investigated the lactate-ammonia response using prolonged exercise and inspiration of hyperoxic gas (60% O2-40% N2). The exercise consisted of either 70-75% maximal O2 uptake (VO2 max) for 40 min (series 1, n = 6) or 75-80% VO2max for 30 min (series 2, n = 6) with the subjects inspiring room air on one occasion and hyperoxia in the other test. In both series blood ammonia rose continuously throughout the exercise regardless of the inspired gas treatment; in contrast blood lactate did not increase after 10 min with room air, and with hyperoxia blood lactate was reduced. Muscle lactate and ammonia (series 2; vastus lateralis) had responses similar to the blood data. The data demonstrated no apparent lactate-ammonia relationship with prolonged exercise or in response to hyperoxia, suggesting that ammonia production can be independent of lactate metabolism. The data also suggest that type I fibers can be a major source of ammonia in humans.     

Metabolic response of perfused livers to various oxygenation conditions

Isolated liver perfusion systems have been used to characterize intrinsic metabolic changes in liver as a result of various perturbations, including systemic injury, hepatotoxin exposure, and warm ischemia. Most of these studies were done using hyperoxic conditions (95% O(2)) but without the use of oxygen carriers in the perfusate. Prior literature data do not clearly establish the impact of oxygenation, and in particular that of adding oxygen carriers to the perfusate, on the metabolic functions of the liver. Therefore, herein the effects of oxygen delivery in the perfusion system on liver metabolism were investigated by comparing three modes of oxygenation. Rat livers were perfused via the portal and hepatic veins at a constant flow rate of 3 mL/min/g liver in a recirculating perfusion system. In the first group, the perfusate was equilibrated in a membrane oxygenator with room air (21% O(2)) before entering the liver. In the second group, the perfusate was equilibrated with a 95% O(2)/5% CO(2) gas mixture. In the third group, the perfusate was supplemented with washed bovine red blood cells (RBCs) at 10% hematocrit and also equilibrated with the 95% O(2)/5% CO(2) gas mixture. Oxygen and CO(2) gradients across the liver were measured periodically with a blood gas analyzer. The rate of change in the concentration of major metabolites in the perfusate was measured over time. Net extracellular fluxes were calculated from these measurements and applied to a stoichiometric-based optimization problem to determine the intracellular fluxes and active pathways in the perfused livers. Livers perfused with RBCs consumed oxygen at twice the rate observed using hyperoxic (95% O(2)) perfusate without RBCs, and also produced more urea and ketone bodies. At the flow rate used, the oxygen supply in perfusate without RBCs was just sufficient to meet the average oxygen demand of the liver but would be insufficient if it increased above baseline, as is often the case in response to environmental perturbations. Metabolic pathway analysis suggests that significant anaerobic glycolysis occurred in the absence of RBCs even using hyperoxic perfusate. Conversely, when RBCs were used, glucose production from lactate and glutamate, as well as pathways related to energy metabolism were upregulated. RBCs also reversed an increase in PPP fluxes induced by the use of hyperoxic perfusate alone. In conclusion, the use of oxygen carriers is required to investigate the effect of various perturbations on liver metabolism.     

Dynamics of noninvasively estimated microvascular O2 extraction during ramp exercise.

Utilization of near-infrared spectroscopy (NIRS) in clinical exercise testing to detect microvascular abnormalities requires characterization of the responses in healthy individuals and theoretical foundation for data interpretation. We examined the profile of the deoxygenated hemoglobin signal from NIRS {deoxygenated hemoglobin + myoglobin [deoxy-(Hb+Mb)] approximately O(2) extraction} during ramp exercise to test the hypothesis that the increase in estimated O(2) extraction would be close to hyperbolic, reflecting a linear relationship between muscle blood flow (Q(m)) and muscle oxygen uptake (Vo(2)(m)) with a positive Q(m) intercept. Fifteen subjects (age 24 +/- 5 yr) performed incremental ramp exercise to fatigue (15-35 W/min). The deoxy-(Hb+Mb) response, measured by NIRS, was fitted by a hyperbolic function [f(x) = ax/(b + x), where a is the asymptotic value and b is the x value that yields 50% of the total amplitude] and sigmoidal function {f(x) = f(0) + A/[1 + e(-(-c+dx))], where f(0) is baseline, A is total amplitude, and c is a constant dependent on d, the slope of the sigmoid}, and the goodness of fit was determined by F test. Only one subject demonstrated a hyperbolic increase in deoxy-(Hb+Mb) (a = 170%, b = 193 W), whereas 14 subjects displayed a sigmoidal increase in deoxy-(Hb+Mb) (f(0) = -7 +/- 7%, A = 118 +/- 16%, c = 3.25 +/- 1.14, and d = 0.03 +/- 0.01). Computer simulations revealed that sigmoidal increases in deoxy-(Hb+Mb) reflect a nonlinear relationship between microvascular Q(m) and Vo(2)(m) during incremental ramp exercise. The mechanistic implications of our findings are that, in most healthy subjects, Q(m) increased at a faster rate than Vo(2)(m) early in the exercise test and slowed progressively as maximal work rate was approached.     

Time course of muscular blood metabolites during forearm rhythmic exercise in hypoxia

O2 concentration, PO2, PCO2, pH, osmolarity, lactate (LA), and hemoglobin (Hb) concentrations in deep forearm venous blood were repeatedly measured during submaximal exercise of forearm muscles. Concentrations of arterial blood gases were determined at rest and during exercise. Experiments were conducted under normoxia and hypobaric hypoxia (PB = 465 Torr). In arterial blood, data obtained during exercise were the same as those obtained during rest under either normoxia or hypoxia. In venous muscular blood, PO2 and O2 concentration were lower at rest and during exercise in hypoxia. The muscular arteriovenous O2 difference during exercise in hypoxia was increased by no more than 10% compared with normoxia, which implied that muscular blood flow during exercise also increased by the same percentage, if we assume that exercise O2 consumption was not affected by hypoxia. Despite increased [LA], the magnitude of changes in PCO2 and pH in hypoxia were smaller than in normoxia during exercise and recovery; this finding is probably due to the increased blood buffer value induced by the greater amount of reduced Hb in hypoxia. Hence all the changes occurring in hypoxia showed that local metabolism was less affected than we expected from the decrease in arterial PO2. The rise in [Hb] that occurred during exercise was lower in hypoxia. Possible underlying mechanisms of the [Hb] rise during exercise are discussed.     

The effect of oxygen and adenosine on lizard thermoregulation

A regulated decrease in internal body temperature (Tb) appears to play a protective role against metabolic disruptions such as exposure to ambient hypoxia. This study examined the possibility that Tb depression is initiated when low internal oxygen levels trigger the release of adenosine, a neural modulator known to influence thermoregulation. We measured selected Tb of Anolis sagrei in a thermal gradient under varied ambient oxygen conditions and following the administration of the adenosine receptor antagonist 8-cyclopentyltheophylline (CPT). The average decrease in Tb observed following exposure to hypoxia (<10% O2) and following exhaustive exercise were 5 degrees and 3 degrees C, respectively, suggesting a role of oxygen availability on initiation of regulated hypothermia. When A. sagrei were run to exhaustion and recovered in hyperoxic (>95% O2) conditions, exercise-induced Tb depression was abolished. Administration of CPT similarly abolished decreased Tb due to both exercise and hypoxia. Trials using Dipsosaurus dorsalis indicate that elevated ambient oxygen during exercise does not influence blood pH or lactate accumulation, suggesting that these factors do not initiate changes in thermoregulatory setpoint following exhaustive exercise. We suggest that when oxygen is limiting, a decrease in arterial oxygen may trigger the release of adenosine, thereby altering the thermoregulatory setpoint.     

Respiratory adjustments of the unanaesthetized chicken, Gallus domesticus, to elevated metabolism elicited by 2,4-dinitrophenol or cold exposure

The effects of pharmacologically elevated metabolism on ventilation, gaseous exchange and blood gases were studied in spontaneously breathing unanaesthetized decerebrate chickens using 2,4-dinitrophenol (DNP) injected intravenously in successive single doses of 2.5-5.0 mg/kg. These responses were compared with the cardiorespiratory adjustments to elevated metabolism evoked by shivering in conscious birds. Oxygen consumption increased with cumulative amounts of DNP, reaching 275 +/- 30% of control values at the maximum tolerated dose of 10-15 mg/kg. Increases in ventilation matched the changes in oxygen consumption via increases in both breathing frequency and tidal volume. Arterial blood gases and pH remained unchanged. Exposure to cold (Ta = 2 +/- 2 degrees C) caused oxygen consumption to increase to 185 +/- 21% of control values. Respiratory and cardiovascular adjustments were similar to those evoked by DNP and were comparable to those produced by low intensity treadmill exercise (cf. Gleeson and Brackenbury, 1984).     

Dynamics of oxygen tension in the brain and subcutaneous adipose tissue of newborn rats during anoxia and reoxygenation

The oxygen tension (pO2) in the brain and subcutaneous tissue of newborn rats was studied during anoxia and reoxygenation with hyperoxic gas mixtures. The level of pO2 in both tissues during anoxia fell from 10-30 mm Hg to 0 mm Hg. When newborn rats were reoxygenated with 50% or 100% O2, the oxygen tension in the brain and subcutaneous first increased and then decreased in spite of the hyperoxic inhalation. The decrease of pO2 in the subcutaneous during hyperoxia was more pronounced than that in the brain. Data obtained are discussed.     

Influence of different oxygen modes on the blood oxygen transport and prooxidant-antioxidant status during hepatic ischemia/reperfusion

Oxygen supply was corrected in rabbits during the hepatic ischemia/reperfusion by means of different breathing mixtures: hypoxic (14.8 % O(2)+85.2 % N(2)), hyperoxic (78 % O(2)+20.2 % N(2)+ 1.8 % CO(2)), or hypercapnic (5 % CO(2) in air). Hepatic ischemia was induced for 30 min by ligation of hepatic artery, reperfusion period lasted 120 min. Indices of blood oxygen transport (p50(act), pCO(2), pH, pO(2), etc.) and prooxidant-antioxidant balance (Schiff bases, conjugated dienes, catalase, retinol, alpha-tocopherol) were measured in the blood and liver. The severity of reperfusion damage was evaluated by the activities of alanine and aspartate aminotransferases (ALT, AST) in the blood. Hepatic ischemia/reperfusion resulted in higher p50(act) in hepatic venous and mixed venous blood in all experimental groups. The changes of p50(act) were most marked in the hypercapnic group and were the weakest in the hypoxic group. The rise in p50(act) was accompanied by higher levels of lipid peroxidation products, ALT and AST in blood and liver homogenates, and by a simultaneous fall of alpha-tocopherol and retinol concentrations, except in the hypoxic group. Catalase activity at the end of reperfusion increased under normoxia, decreased under hyperoxia or hypercapnia and did not change under hypoxia. The moderate hypoxia during reperfusion was accompanied by a better balance between the mechanisms of reactive oxygen species production and inactivation that may be observed by optimal changes in p50act and reduced the hepatic damage in this pathological condition.     

Effect of mild carboxy-hemoglobin on exercising skeletal muscle: intravascular and intracellular evidence

We studied muscle blood flow, muscle oxygen uptake (VO(2)), net muscle CO uptake, Mb saturation, and intracellular bioenergetics during incremental single leg knee-extensor exercise in five healthy young subjects in conditions of normoxia, hypoxia (H; 11% O(2)), normoxia + CO (CO(norm)), and 100% O(2) + CO (CO(hyper)). Maximum work rates and maximal oxygen uptake (VO(2 max)) were equally reduced by approximately 14% in H, CO(norm), and CO(hyper). The reduction in arterial oxygen content (Ca(O(2))) (approximately 20%) resulted in an elevated blood flow (Q) in the CO and H trials. Net muscle CO uptake was attenuated in the CO trials. Suprasystolic cuff measurements of the deoxy-Mb signal were not different in terms of the rate of signal rise or maximum signal attained with and without CO. At maximal exercise, calculated mean capillary PO(2) was most reduced in H and resulted in the lowest Mb-associated PO(2). Reductions in ATP, PCr, and pH during H, CO(norm), and CO(hyper) occurred earlier during progressive exercise than in normoxia. Thus the effects of reduced Ca(O(2)) due to mild CO poisoning are similar to H.     

Skeletal muscle metabolism is unaffected by DCA infusion and hyperoxia after onset of intense aerobic exercise

This study investigated whether hyperoxic breathing (100% O(2)) or increasing oxidative substrate supply [dichloroacetate (DCA) infusion] would increase oxidative phosphorylation and reduce the reliance on substrate phosphorylation at the onset of high-intensity aerobic exercise. Eight male subjects cycled at 90% maximal O(2) uptake (VO(2 max)) for 90 s in three randomized conditions: 1) normoxic breathing and saline infusion over 1 h immediately before exercise (CON), 2) normoxic breathing and saline infusion with DCA (100 mg/kg body wt), and 3) hyperoxic breathing for 20 min at rest and during exercise and saline infusion (HYP). Muscle biopsies from the vastus lateralis were sampled at rest and after 30 and 90 s of exercise. DCA infusion increased pyruvate dehydrogenase (PDH) activation above CON and HYP (3.10 +/- 0.23, 0.56 +/- 0.08, 0.69 +/- 0.05 mmol x kg wet muscle(-1) x min(-1), respectively) and significantly increased both acetyl-CoA and acetylcarnitine (11.0 +/- 0.7, 2.0 +/- 0.5, 2.2 +/- 0.5 mmol/kg dry muscle, respectively) at rest. However, DCA and HYP did not alter phosphocreatine degradation and lactate accumulation and, therefore, the reliance on substrate phosphorylation during 30 s (CON, 51.2 +/- 5.4; DCA, 56.5 +/- 7.1; HYP, 69.5 +/- 6.3 mmol ATP/kg dry muscle) and 90 s of exercise (CON, 90.6 +/- 9.5; DCA, 107.2 +/- 13.0; HYP, 101.2 +/- 15.2 mmol ATP/kg dry muscle). These data suggest that the rate of oxidative phosphorylation at the onset of exercise at 90% VO(2 max) is not limited by oxygen availability to the active muscle or by substrate availability (metabolic inertia) at the level of PDH in aerobically trained subjects.     

Relationship between muscle fatigue and oxygen uptake during cycle ergometer exercise with different ramp slope increments.

The surface electromyogram (EMG) from active muscle and oxygen uptake (VO2) were studied simultaneously to examine changes of motor unit (MU) activity during exercise tests with different ramp increments. Six male subjects performed four exhausting cycle exercises with different ramp slopes of 10, 20, 30 and 40 W.min-1 on different days. The EMG signals taken from the vastus lateralis muscle were stored on a digital data recorder and converted to obtain the integrated EMG (iEMG). The VO2 was measured, with 20-s intervals, by the mixing chamber method. A non-linear increase in iEMG against work load was observed for each exercise in all subjects. The break point of the linear relationship of iEMG was determined by the crossing point of the two regression lines (iEMGbp). Significant differences were obtained in the exercise intensities corresponding to maximal oxygen uptake (VO2max) and the iEMGbp between 10 and 30, and 10 and 40 W.min-1 ramp exercises (P < 0.05). However, no significant differences were obtained in VO2max and VO2 corresponding to the iEMGbp during the four ramp exercises. With respect to the relationship between VO2 and exercise intensity during the ramp increments, the VO2-exercise intensity slope showed significant differences only for the upper half (i.e. above iEMGbp). These results demonstrated that the VO2max and VO2 at which a nonlinear increase in iEMG was observed were not varied by the change of ramp slopes but by the exercise intensity corresponding to VO2max and the iEMGbp was varied by the change of ramp slopes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of acetazolamide on metabolic and respiratory responses to exercise at maximal O2 uptake

Changes in blood gases, ions, lactate, pH, hemoglobin, blood temperature, total body metabolism, and muscle metabolites were measured before and during exercise (except muscle), at fatigue, and during recovery in normal and acetazolamide-treated horses to test the hypothesis that an acetazolamide-induced acidosis would compromise the metabolism of the horse exercising at maximal O2 uptake. Acetazolamide-treated horses had a 13-mmol/l base deficit at rest, higher arterial Po2 at rest and during exercise, higher arterial and mixed venous Pco2 during exercise, and a 48-s reduction in run time. Arterial pH was lower during exercise but not in recovery after acetazolamide. Blood temperature responses were unaffected by acetazolamide administration. O2 uptake was similar during exercise and recovery after acetazolamide treatment, whereas CO2 production was lower during exercise. Muscle [glycogen] and pH were lower at rest, whereas heart rate, muscle pH and [lactate], and plasma [lactate] and [K+] were lower and plasma [Cl-] higher following exercise after acetazolamide treatment. These data demonstrate that acetazolamide treatment aggravates the CO2 retention and acidosis occurring in the horse during heavy exercise. This could negatively affect muscle metabolism and exercise capacity.     

Cardiopulmonary control during exercise in the duck

To determine the importance of nonhumoral drives to exercise hyperpnea in birds, we exercised adult White Pekin ducks on a treadmill (3 degrees incline) at 1.44 km X h-1 for 15 min during unidirectional artificial ventilation. Intrapulmonary gas concentrations and arterial blood gases could be regulated with this ventilation procedure while allowing ventilatory effort to be measured during both rest and exercise. Ducks were ventilated with gases containing either 4.0 or 5.0% CO2 in 19% O2 (balance N2) at a flow rate of 12 l X min-1. At that flow rate, arterial CO2 partial pressure (PaCO2) could be maintained within +/- 2 Torr of resting values throughout exercise. Arterial O2 partial pressure did not change significantly with exercise. Heart rate, mean arterial blood pressure, and mean right ventricular pressure increased significantly during exercise. On the average, minute ventilation (used as an indicator of the output from the central nervous system) increased approximately 400% over resting levels because of an increase in both tidal volume and respiratory frequency. CO2-sensitivity curves were obtained for each bird during rest. If the CO2 sensitivity remained unchanged during exercise, then the observed 1.5 Torr increase in PaCO2 during exercise would account for only about 6% of the total increase in ventilation over resting levels. During exercise, arterial [H+] increased approximately 4 nmol X l-1; this increase could account for about 18% of the total rise in ventilation. We conclude that only a minor component of the exercise hyperpnea in birds can be accounted for by a humoral mechanism; other factors, possibly from muscle afferents, appear responsible for most of the hyperpnea observed in the running duck.     

Perivascular nitric oxide and superoxide in neonatal cerebral hypoxia-ischemia

Decreased cerebral blood flow (CBF) has been observed following the resuscitation from neonatal hypoxic-ischemic injury, but its mechanism is not known. We address the hypothesis that reduced CBF is due to a change in nitric oxide (NO) and superoxide anion O(2)(-) balance secondary to endothelial NO synthase (eNOS) uncoupling with vascular injury. Wistar rats (7 day old) were subjected to cerebral hypoxia-ischemia by unilateral carotid occlusion under isoflurane anesthesia followed by hypoxia with hyperoxic or normoxic resuscitation. Expired CO(2) was determined during the period of hyperoxic or normoxic resuscitation. Laser-Doppler flowmetry was used with isoflurane anesthesia to monitor CBF, and cerebral perivascular NO and O(2)(-) were determined using fluorescent dyes with fluorescence microscopy. The effect of tetrahydrobiopterin supplementation on each of these measurements and the effect of apocynin and N(omega)-nitro-L-arginine methyl ester (L-NAME) administration on NO and O(2)(-) were determined. As a result, CBF in the ischemic cortex declined following the onset of resuscitation with 100% O(2) (hyperoxic resuscitation) but not room air (normoxic resuscitation). Expired CO(2) was decreased at the onset of resuscitation, but recovery was the same in normoxic and hyperoxic resuscitated groups. Perivascular NO-induced fluorescence intensity declined, and O(2)(-)-induced fluorescence increased in the ischemic cortex after hyperoxic resuscitation up to 24 h postischemia. L-NAME treatment reduced O(2)(-) relative to the nonischemic cortex. Apocynin treatment increased NO and reduced O(2)(-) relative to the nonischemic cortex. The administration of tetrahydrobiopterin following the injury increased perivascular NO, reduced perivascular O(2)(-), and increased CBF during hyperoxic resuscitation. These results demonstrate that reduced CBF follows hyperoxic resuscitation but not normoxic resuscitation after neonatal hypoxic-ischemic injury, accompanied by a reduction in perivascular production of NO and an increase in O(2)(-). The finding that tetrahydrobiopterin, apocynin, and L-NAME normalized radical production suggests that the uncoupling of perivascular NOS, probably eNOS, due to acquired relative tetrahydrobiopterin deficiency occurs after neonatal hypoxic-ischemic brain injury. It appears that both NOS uncoupling and the activation of NADPH oxidase participate in the changes of reactive oxygen concentrations seen in cerebral hypoxic-ischemic injury.     

Cerebrospinal fluid acid-base balance during muscular exercise

Ventilation, metabolism, arterial blood gases, and blood and cerebrospinal fluid (CSF) acid-base status were measured in exercise studies on seven ponies during mild, moderate, and near-maximal treadmill exercise. CSF and arterial blood were sampled via indwelling catheters. Generally measurements were made during the 3rd, 6th, and 9th minute of steady-state exercise, with CSF sampled only during the 9th minute. Alveolar ventilation (VA) and metabolic rate (VO2) increased proportionately during exercise below the anaerobic threshold, but above this threshold, VA increased at a faster rate than VO2. The similarity of these response to those observed in man suggests the pony is a suitable animal model for study of exercise hyperpnea. No change in CSF acid-base balance occurred with light-to-moderate work; however, with near-maximal work a fall in CSF carbon dioxide partial pressure due to hyperventilation caused CSF to become alkaline (pH = 7.380) relative to rest (pH = 7.330). CSF lactate increased slightly with exercise but had no effect on CSF [HCO3-], which remained constant from rest to severe exercise. We conclude that it is unlikely the hyperpnea at any intensity of exercise results from an increased H+ stimulation at the medullary chemoreceptor.     

Effects of hyperoxia on skeletal muscle carbohydrate metabolism during transient and steady-state exercise.

This study compared the effects of inspiring either a hyperoxic (60% O(2)) or normoxic gas (21% O(2)) while cycling at 70% peak O(2) uptake on 1) the ATP derived from substrate phosphorylation during the initial minute of exercise, as estimated from phosphocreatine degradation and lactate accumulation, and 2) the reliance on carbohydrate utilization and oxidation during steady-state cycling, as estimated from net muscle glycogen use and the activity of pyruvate dehydrogenase (PDH) in the active form (PDH(a)), respectively. We hypothesized that 60% O(2) would decrease substrate phosphorylation at the onset of exercise and that it would not affect steady-state exercise PDH activity, and therefore muscle carbohydrate oxidation would be unaltered. Ten active male subjects cycled for 15 min on two occasions while inspiring 21% or 60% O(2), balance N(2). Blood was obtained throughout and skeletal muscle biopsies were sampled at rest and 1 and 15 min of exercise in each trial. The ATP derived from substrate-level phosphorylation during the initial minute of exercise was unaffected by hyperoxia (21%: 52.2 +/- 11.1; 60%: 54.0 +/- 9.5 mmol ATP/kg dry wt). Net glycogen breakdown during 15 min of cycling was reduced during the 60% O(2) trial vs. 21% O(2) (192.7 +/- 25.3 vs. 138.6 +/- 16.8 mmol glycosyl units/kg dry wt). Hyperoxia had no effect on PDH(a), because it was similar to the 21% O(2) trial at rest and during exercise (21%: 2.20 +/- 0.26; 60%: 2.25 +/- 0.30 mmol.kg wet wt(-1).min(-1)). Blood lactate was lower (6.4 +/- 1.0 vs. 8.9 +/- 1.0 mM) at 15 min of exercise and net muscle lactate accumulation was reduced from 1 to 15 min of exercise in the 60% O(2) trial compared with 21% (8.6 +/- 5.1 vs. 27.3 +/- 5.8 mmol/kg dry wt). We concluded that O(2) availability did not limit oxidative phosphorylation in the initial minute of the normoxic trial, because substrate phosphorylation was unaffected by hyperoxia. Muscle glycogenolysis was reduced by hyperoxia during steady-state exercise, but carbohydrate oxidation (PDH(a)) was unaffected. This closer match between pyruvate production and oxidation during hyperoxia resulted in decreased muscle and blood lactate accumulation. The mechanism responsible for the decreased muscle glycogenolysis during hyperoxia in the present study is not clear.