Net flux of glucose, lactate, volatile fatty acids, and nitrogen metabolites across the portal-drained viscera and liver of pregnant ewes

Our objective for this study was to determine the pattern of nutrient flux across the portal-drained viscera (PDV) and liver in ewes with varying numbers of fetuses. Catheters were placed in the hepatic portal vein, a branch of the hepatic vein, a mesenteric vein, and the abdominal aorta of ewes. Blood flow and net nutrient release across the PDV and liver were determined before exposure to rams. Ewes were then mated, which resulted in two ewes not pregnant and in six ewes with single and 11 ewes with twin lambs. Additional measurements were taken 103, 82, 61, 39, 19, and 6 d before parturition. Net PDV glucose release did not differ from zero (-.4 +/- 8.4 mmol/h; P = .58). In ewes with singles, premating net hepatic glucose release was 34.4 +/- 2.4 mmol/h, and 19 d before parturition it was 46.2 +/- 3.8 mmol/h. In ewes with twins, premating net hepatic glucose release was 36.8 +/- 2.7 mmol/h, and 19 d before parturition it was 47.4 +/- 2.8 mmol/h. Net PDV lactate release did not differ with litter size (P = .58) or days from parturition (P = .14; 9.7 +/- 4.6 mmol/h). Net lactate uptake by the liver increased in pregnant ewes as the pregnancy progressed (P < .001). The hepatic extraction ratio for lactate increased in late pregnancy (P = .02). Net PDV and hepatic release of acetate and propionate were not different with litter size or days from parturition. Hepatic extraction ratios of VFA did not differ with litter size or day from parturition. The patterns of change in hepatic metabolite fluxes are similar to the patterns of change in gravid uterus metabolite uptake. Hepatic lactate uptake seems to be regulated during pregnancy.     

Small amounts of fructose markedly augment net hepatic glucose uptake in the conscious dog

Fructose activates glucokinase by releasing the enzyme from its inhibitory protein in liver. To examine the importance of acute activation of glucokinase in regulating hepatic glucose uptake, the effect of intraportal infusion of a small amount of fructose on net hepatic glucose uptake (NHGU) was examined in 42 h-fasted conscious dogs. Isotopic ([3-3H] and [U-14C]glucose) and arteriovenous difference methods were used. Each study consisted of an equilibration period (-90 to -30 min), a control period (-30 to 0 min), and a hyperglycemic/hyperinsulinemic period (0-390 min). During the latter period, somatostatin (489 pmol x kg(-1) x min(-1)) was given, along with intraportal insulin (7.2 pmol x kg(-1) x min(-1)) and glucagon (0.5 ng x kg(-1) x min(-1)). In this way, the liver sinusoidal insulin level was fixed at four times basal (456 +/- 60 pmol/l), and liver sinusoidal glucagon level was kept basal (46 +/- 6 ng/l). Glucose was infused through a peripheral vein to create hyperglycemia (12.5 mmol/l plasma). Hyperglycemic hyperinsulinemia (no fructose) switched net hepatic glucose balance (micromoles per kilogram per minute) from output (11.3 +/- 1.4) to uptake (14.7 +/- 1.7) and net lactate balance (micromoles per kilogram per minute) from uptake (6.5 +/- 2.1) to output (4.4 +/- 1.5). Fructose was infused intraportally at a rate of 1.7, 3.3, or 6.7 micromol x kg(-1) x min(-1), starting at 120, 210, or 300 min, respectively. In the three periods, portal blood fructose increased from <6 to 113 +/- 14, 209 +/- 29, and 426 +/- 62 micromol/l, and net hepatic fructose uptake increased from 0.03 +/- 0.01 to 1.3 +/- 0.4, 2.3 +/- 0.7, and 5.1 +/- 0.6 micromol x kg(-1) x min(-1), respectively. NHGU increased to 41 +/- 3, 54 +/- 5, and 69 +/- 8 micromol x kg(-1) x min(-1), respectively, and net hepatic lactate output increased to 11.0 +/- 3.2, 15.3 +/- 2.7, and 22.4 +/- 2.8 micromol x kg(-1) x min(-1) in the three fructose periods, respectively. The amount of [3H]glucose incorporated into glycogen was equivalent to 69 +/- 3% of [3H]glucose taken up by the liver. These data suggest that glucokinase translocation within the hepatocyte is a major determinant of hepatic glucose uptake by the dog in vivo.     

Direct antagonism of ethanol''s effects on GABA(A) receptors by increased atmospheric pressure

We investigated hepatic blood flow, O2 exchange and metabolism in porcine endotoxic shock (Control, n = 8; Endotoxin, n = 10) with administration of hydroxyethylstarch to maintain arterial pressure (MAP)>60 mmHg. Before and 12, 18 and 24 h after starting continuous i.v. endotoxin we measured portal venous and hepatic arterial blood flow, intracapillary haemoglobin O2 saturation (Hb-O2%) of the liver surface and arterial, portal and hepatic venous lactate, pyruvate, glycerol and alanine concentrations. Glucose production rate was derived from the plasma isotope enrichment during infusion of [6,6-2H2]-glucose. Despite a sustained 50% increase in cardiac output endotoxin caused a progressive, significant fall in MAP. Liver blood flow significantly increased, but endotoxin affected neither hepatic O2 delivery and uptake nor mean intracapillary Hb-O2% and Hb-O2% frequency distributions. Endotoxin nearly doubled endogenous glucose production rate while hepatic lactate, alanine and glycerol uptake rates progressively decreased significantly. The lactate uptake rate even became negative (P<0.05 vs Control). Endotoxin caused portal and hepatic venous pH to fall significantly concomitant with significantly increased arterial, portal and hepatic venous lactate/pyruvate ratios. During endotoxic shock increased cardiac output achieved by colloid infusion maintained elevated liver blood flow and thereby macro- and microcirculatory O2 supply. Glucose production rate nearly doubled with complete dissociation of hepatic uptake of glucogenic precursors and glucose release. Despite well-preserved capillary oxygenation increased lactate/pyruvate ratios reflecting impaired cytosolic redox state suggested deranged liver energy balance, possibly due to the O2 requirements of gluconeogenesis.     

Blood lactate and acid-base balance in graded neonatal hypoxia: evidence for oxygen-restricted metabolism

This study examines the neonatal response to graded hypoxia and determines the arterial PO2 (PaO2) threshold for oxygen-restricted metabolism as confirmed by the development of lactic acidosis and altered oxygen handling. Anesthetized, intubated, and ventilated 3-day-old pigs (n = 56) were randomly assigned to one of five predetermined acute (120 min) graded hypoxia groups: normoxia (PaO2 = 80 Torr) or mild (60 Torr), moderate (40 Torr), moderately severe (30 Torr), or severe (20 Torr) hypoxia. In moderate hypoxia, lactate and acid-base homeostasis were unaltered due to a significant increase in oxygen extraction (P < 0.05) that was sufficient to maintain the arteriovenous oxygen content difference (oxygen uptake). In moderately severe hypoxia, increased arterial lactate and decreased HCO3- and base excess were evidence of anaerobic metabolism, yet pH was unaltered, indicating adequate buffering. In this group, despite the increase in oxygen extraction, oxygen uptake was reduced, indicating the onset of oxygen-restricted metabolism. The severe hypoxia group had significantly increased lactate (21.7 +/- 3.9 mmol/l), decreased pH (7.01 +/- 0.07) and base excess (-21.5 +/- 3.0 mmol/l), and depletion of HCO3- (9.7 +/- 1.6 mmol/l) (P < 0.0001). Here, increases in oxygen extraction were severely limited by availability, resulting in significantly reduced oxygen uptake, anaerobic metabolism, and profound lactic acidosis.     

Lactate turnover in rat glioma measured by in vivo nuclear magnetic resonance spectroscopy

Elevated tissue lactate concentrations typically found in tumors can be measured by in vivo nuclear magnetic resonance (NMR) spectroscopy. In this study, lactate turnover in rat C6 glioma was determined from in vivo 1H NMR measurements of [3-13C]lactate buildup during steady-state hyperglycemia with [1-13C]glucose. With this tumor model, a narrow range of values was observed for the first-order rate constant that describes lactate efflux, k2 = 0.043 +/- 0.007 (n = 12) SD min-1. For individual animals, the standard error in k2 was small (< 18%), which indicated that the NMR data fit the kinetic model well. Lactate measurements before and after infusing [1-13C]glucose showed that the majority of the tumor lactate pool was metabolically active. Signals from 13C-labeled glutamate in tumors were at least 10-fold smaller than the [3-13C]lactate signal, whereas spectra of the contralateral hemispheres revealed the expected labeling of [4-13C]glutamate, as well as [2-13C] and [3-13C]glutamate, which indicates that label cycled through the tricarboxylic acid cycle in the brain tissue. Lack of significant 13C labeling of glutamate was consistent with low respiratory metabolism in this glioma. It is concluded that lactate in rat C6 glioma is actively turning over and that the kinetics of lactate efflux can be quantified noninvasively by 1H NMR detection of 13C label. This noninvasive NMR approach may offer a valuable tool to help evaluate tumor growth and metabolic responsiveness to therapies.     

Release of lactate by the lung in acute lung injury

The pathogenesis of hyperlactatemia during sepsis is poorly understood. We have previously described an increase in lactate concentration across the lung in the dog during early endotoxemia. Accordingly, we sought to determine if the lung releases lactate in humans and what relation this has with lung injury. METHODS: We measured lactate concentrations across the lung and lung injury scores (LIS) in two groups of patients. Group 1 consisted of nine patients with acute lung injury (LIS > or = 2.0) and elevated lactate concentrations (> 2.0 mmol/L). Group 2 contained 12 patients with no acute lung injury (LIS scores < or = 1.5), with or without increased lactate concentrations. Simultaneous measurements of plasma lactate and blood gases were obtained from indwelling arterial and pulmonary artery catheters. Measurements of cardiac output were also obtained. Lactate measurements were done using a lactate analyzer (YSI; Yellow Springs, Ohio). RESULTS: For each patient with acute lung injury and hyperlactatemia, an arterial-venous lactate gradient existed demonstrating release of lactate by the lung. This gradient persisted after correction for changes in hemoconcentration across the lung. The lactate gradient across the lung was 0.4 +/- 0.2 mmol/L for group 1 vs 0.05 +/- 0.1 mmol/L for group 2 (p = 0.001). This corresponded to a mean pulmonary lactate flux of 231.3 +/- 211.3 vs 5.0 +/- 37.2 mmol/h (p = 0.001). The lactate flux and the arterial-venous lactate difference correlated with LIS both for the entire sample and for the subgroup with hyperlactatemia (r = 0.69, p < 0.01). Pulmonary lactate flux was not related to arterial lactate levels (r = 0.25). CONCLUSION: In patients with acute lung injury and hyperlactatemia, the lung is a major source of lactate and lactate flux correlates with LIS. This lactate flux could explain some of the hyperlactatemia seen in sepsis.     

Short-latency EMG potentials elicited by head taps in sternocleidomastoid muscles: a study on normal human subjects and patients with central or vestibular lesions

Ten subjects with diabetes mellitus and unilateral chronic foot ulcer were investigated. Local tissue concentrations of glucose and lactate were measured using the microdialysis method at a distance of 0.5-1 cm from the edge of the ulcer and in normal skin in the contralateral foot. Subcutaneous blood flow in the area investigated was measured using the 133Xewashout technique. The interstitial glucose concentration in the ulcer was found to be lower than in intact skin (8.0 +/- 1.0 mmol l-1 vs. 8.5 +/- 1.1 mmol l-1) (P < 0.02), and the interstitial lactate concentration was higher in the ulcer than in intact skin (3.2 +/- 0.2 mmol l-1 vs. 2.1 +/- 0.3 mmol l-1) (P < 0.01). The subcutaneous blood flow was on average 40% higher in the ulcer than in the intact skin. The calculated local glucose uptake and lactate outputs were twofold higher in the ulcer than in the intact skin. However, the molar ratio between lactate output and glucose uptake was approximately two, both in the ulcer and in the intact skin, indicating that the glucose metabolism was qualitatively the same in the two regions.     

Studies of lysophospholipids related to the hamster sperm acrosome reaction in vitro

1. One of the metabolic features of acquired immunodeficiency syndrome is increased tissue glucose uptake documented by euglycaemic-hyperinsulinaemic clamp studies, suggesting increased insulin sensitivity. However, these results may also be related to the confounding effect of increased non-insulin-mediated glucose uptake in acquired immunodeficiency syndrome, which will result in an erroneously presumed increased insulin sensitivity. To study the contribution of non-insulin-mediated glucose uptake to total tissue glucose uptake in acquired immunodeficiency syndrome, we conducted a hypoinsulinaemic clamp study in clinically stable human immunodeficiency virus-infected (Centers for Disease Control class IV) men (n = 7) and healthy subjects (n = 5). Glucose uptake was measured by a primed, continuous infusion of [3-3H]glucose in the postabsorptive state and during somatostatin-induced insulinopenia at euglycaemic (approximately 5.3 mmol/l) and hyperglycaemic (approximately 11 mmol/l) glucose concentrations. 2. Basal glucose concentration (patients, 5.2 +/- 0.1 mmol/l; control subjects, 5.3 +/- 0.1 mmol/l) and basal glucose tissue uptake (patients, 15.9 +/- 0.5 mumol min-1 kg-1 fat-free mass; control subjects, 15.2 +/- 0.4 mumol min-1 kg-1 fat-free mass) were not different between the two groups. 3. Euglycaemic glucose uptake during somatostatin infusion, reflecting non-insulin-mediated glucose uptake, decreased to 82 +/- 3% in patients and 78 +/- 2% in control subjects (not significant). Under hyperglycaemic (approximately 11 mmol/l) conditions with sustained insulinopenia, no differences in glucose uptake existed between the two groups (patients, 16.8 +/- 0.6 mumol min-1 kg-1 fat-free mass; control subjects, 16.1+/- 0.3 mumol min-1 kg-1 fat-free mass).(ABSTRACT TRUNCATED AT 250 WORDS)     

Myocardial glucose uptake and breakdown during adenosine-induced vasodilation

In isolated K+ (16.2 mM)-arrested cat hearts perfused at constant pressure adenosine infusions (0.8 mumoles - min-1 - 100 g-1 for 10 min) caused an increase in myocardial 14C-glucose uptake and release of 14CO2 + H14CO3- AND 14C-lactate simultaneously with a rise in coronary flow. The ratio of the release of 14CO2 + H14CO3- to that of 14C-lactate and the specific activity of lactate in the effuate were not altered. In K+ -arrested hearts perfused with constant volume neither glucose uptake nor glucose breakdown were influenced by 0.8 or 100 mumoles - min-1 - 100 g-1 adenosine with 0.1 - 5 mM glucose in the perfusion medium. It is concluded that adenosine does not affect directly the myocardial glucose carrier system, aerobic or anaerobic glucose breakdown or glycogenolysis, but enhances glucose uptake secondarily by increasing coronary flow. This interpretation is substantiated by the finding that mechanically produced increases in perfusion volume caused similar increases in myocardial glucose uptake as were observed with comparable adenosine-induced coronary flow increments.     

Small changes in extracellular sodium influence myogenic tone in rabbit facial vein by changing its sensitivity to calcium

Extracellular Na+ concentration ([Na+]e) significantly effects the regulation of myogenic tone in isolated blood vessels. We examined the effect of small changes in [Na+]e on simultaneous changes in stretch-activated myogenic tone in rabbit facial vein and 45Ca2+ unidirectional influx and net uptake. Decreasing [Na+]e from 150 to 120 mmol/l augmented myogenic tone (control: 3.15 +/- 0.27 mN, n = 22) by 89 +/- 29%, while raising [Na+]e to 165 mmol/l attenuated myogenic tone to 80 +/- 2% of control. Changes in myogenic tone induced by alterations in [Na+]e were not accompanied by proportional changes in 45Ca2+ net uptake. 45Ca2+ unidirectional influx per unit of wall force (10.2 +/- 1.0 pmol/mg per mN force, n = 22, control) was decreased to 6.1 +/- 0.6 pmol/mg per mN (n = 20, P < 0.05) and increased to 21.0 +/- 2.5 pmol/mg per mN (n = 14, P < 0.05) when [Na+]e was 120 or 165 mmol/l, respectively, suggesting that decreasing [Na+]e is related to an increased sensitivity to calcium. We conclude that, in the rabbit facial vein, the sensitivity of myogenic tone to changes in [Na+]e may reflect changes in the sensitivity of smooth muscle to Ca2+ through a change in mechanoreceptor sensitivity.     

Modification of hypoxia-induced injury in cultured rat astrocytes by high levels of glucose

BACKGROUND AND PURPOSE: Preexisting hyperglycemia exacerbates central nervous system injury after transient global and focal cerebral ischemia. Increased anaerobic metabolism with resultant lactic acidosis has been shown to cause the hyperglycemic, neuronal injury. The contribution of astrocytes in producing lactic acidosis under hyperglycemic/ischemic conditions is unclear, whereas the protective role of astrocytes in ischemic-induced neuronal injury has been documented. The ability of astrocytes to maintain energy status and ion homeostasis under hyperglycemic conditions could ultimately reduce neuronal injury. Therefore, we determined the effects of increased glucose concentrations on glucose utilization, lactate production, extracellular pH, and adenosine triphosphate concentrations in hypoxia-treated astrocyte cultures. METHODS: Primary astrocytes were prepared from neonatal rat cerebral cortices. After 35 days in vitro, cultures were incubated with 0-60 mmol/L glucose and subjected to hypoxic conditions at 95% N2/5% CO2 for 24 hours. In addition, under high-glucose conditions (30 mmol/L), astrocytes were exposed to up to 72 hours of hypoxia. Determination of lactate dehydrogenase efflux, adenosine triphosphate concentrations, and extracellular lactate concentrations defined astrocyte status. Equiosmolar levels of mannitol were added in place of high glucose concentrations to distinguish hyperosmotic effect. RESULTS: When physiological concentrations of glucose (7.5 mmol/L) or lower concentrations were used, significant cell damage occurred with 24 hours of hypoxia, as determined by increased efflux of lactate dehydrogenase and loss of cell protein. When higher glucose concentrations (15-60 mmol/L) were used, efflux of lactate dehydrogenase was similar to that observed in normoxic cultures, despite an increased utilization of glucose. Lactate concentrations in the media at low or normal glucose concentrations exceeded normoxic levels, but higher glucose concentrations (15-30 mmol/L) failed to increase lactate levels further. Values of adenosine triphosphate for hypoxic astrocytes treated with high glucose concentrations were significantly higher than those of astrocytes with zero or low glucose levels. In cultures exposed to hypoxia and high glucose levels (30 mmol/L), no cellular injury was observed before 48 hours of hypoxia. Lactate concentrations in the media increased during the first 24 hours of hypoxia and reached steady state. The pH of the media decreased to 6.4 after 24 hours and 5.5 at 48 hours. The latter pH was concomitant with a marked increase in extracellular lactate dehydrogenase activity. Hyperosmotic mannitol failed to protect cultured astrocytes against hypoxia. CONCLUSIONS: Hypoxic injury to mature astrocytes was reduced by the presence of 15-60 mmol/L glucose in the medium during 24-30 hours of hypoxia. Injury occurred when the pH of the medium was < 5.5. This protection was not afforded by the hyperosmotic effect of high glucose concentrations, nor was the hypoxic injury at later time periods with 30 mmol/L glucose mediated solely by lactate accumulation.     

Impact of impaired coronary flow reserve and insulin resistance on myocardial energy metabolism in patients with syndrome X

To evaluate the role of a decreased coronary flow reserve in the genesis of angina pectoris in patients with syndrome X, we studied myocardial hemodynamics and metabolism at rest, during pace stress, and in the recovery period after pacing in 18 consecutive patients with syndrome X and in 10 control subjects. By means of positron emission tomography or the intracoronary flow-wire method, patients were subclassified as having microvascular angina (MA, n = 8) when coronary flow reserve was reduced (<2.5) or no microvascular angina (non-MA, n = 10) when coronary flow reserve was preserved (> or =2.5). At rest, coronary sinus blood flow was increased in MA patients. During pace stress, coronary sinus blood flow increased by 39 +/- 6% in MA patients versus 67 +/- 12% in non-MA patients and 69 +/- 7% in controls (p <0.05). Patients with non-MA revealed fasting hyperinsulinemia, increased arterial concentration of free fatty acids, and a similar tendency for beta-hydroxybutyrate. Oxygen extraction and carbon dioxide release did not differ between groups. Net myocardial lactate release was not observed in any patient during pace stress and myocardial energy metabolism was preserved in all patients with syndrome X. During pacing, myocardial uptake of free fatty acids and beta-hydroxybutyrate was increased in non-MA patients. Myocardial uptake of free fatty acids correlated positively and myocardial glucose and lactate uptake correlated inversely with arterial concentrations of free fatty acids in all subjects. Metabolic evidence of myocardial ischemia is uncommon in patients with syndrome X, irrespective of a globally reduced coronary flow reserve. Although patients with syndrome X can be subclassified according to presence of a microvascular or a metabolic disorder, angina pectoris and ST-segment depressions coexist with a preserved global myocardial energy efficiency in all patients.     

The effect of the hepatic nerves on the disposition of a mixed meal by conscious dogs

We examined the disposition of a mixed meal by nine conscious dogs fasted for 24 hours with surgical hepatic denervation. The results were compared with those from identical studies carried out previously in 13 hepatic-innervated dogs. Net gut release of glucose and gluconeogenic precursors (assessed with the arteriovenous difference technique), the resulting blood glucose and plasma insulin concentrations, and the hepatic glucose load were remarkably similar in the two groups. Net hepatic glucose uptake was 4.8 +/- 3.6 g in hepatic-denervated and 7.7 +/- 3.3 g in hepatic-innervated dogs. Cumulative net hepatic lactate release in hepatic-denervated dogs was 4.3 +/- 1.4 g of glucose equivalents, half the value for hepatic-innervated dogs. Net hepatic carbon intake was similar in the two groups. Hepatic lipogenesis, oxidation, and net glycogen synthesis were qualitatively similar between groups. In conclusion, the disposition of a mixed meal by hepatic-innervated and hepatic-denervated dogs was very similar. Subtle alterations in net hepatic balance of substrates (tendencies toward decreases in net hepatic glucose uptake and lactate release) made net carbon retention in denervated livers virtually identical with that in innervated livers. When other compensatory mechanisms are intact, hepatic denervation does not significantly alter hepatic disposition of a mixed meal.     

Determination of 14CO2 in breath and 14C in stool after oral administration of cholyl-1-[14C]glycine: clinical application

Twenty patients with intestinal bacterial overgrowth and 20 control subjects were investigated for bile acid deconjugation, by measuring 14CO2 in the breath after cholyl-1-[14C]glycine administration. 14CO2 output/24h was 11.0 +/- 5.2% (mean +/- SD) in controls and 54.2 +/- 14.0% (mean +/- SD) in bacterial-overgrowth patients (P less than .001). 14CO2 excretion rate in 12h, when normalized to 100% of the dose at the 12th hour, gave an even finer discrimination between the two groups (no false responses). 14C in stool, analyzed in 20 malabsorption patients and 20 controls by two different techniques, was 6.6 +/- 4% and 31.38 +/- 21.7% (mean +/- SD), respectively. Results by the two different techniques described here correlated well (r = .99). Bile acid malabsorption was in reasonable agreement (r = .67) with percentage of "chenoid" (chenodeoxycholic acid plus ursodeoxycholic acid) in the stool by gas-liquid chromatography; a poorer correlation was observed when "chenoid" plus "choloid" (cholic acid plus its epimers) were plotted vs. -4C in stool (r = .57, n = 15).     

Age-related changes in oxygen and nutrient uptake by hindquarters in newborn pigs during cold-induced shivering

Newborn pigs rely essentially on shivering thermogenesis in the cold. In order to understand the rapid postnatal enhancement of thermogenic capacities in piglets, the oxygen and nutrient uptake of hindquarters was measured in vivo in 1- (n = 6) and 5-day-old (n = 6) animals at thermal neutrality and during cold exposure. The hindquarters were considered to represent a skeletal muscle compartment. Indirect calorimetry and arterio-venous techniques were used. The cold challenge (23 C at 1 day old and 15 C at 5 days old for 90 min) induced a similar increase (+90 %) in regulatory heat production at both ages. Hindquarters blood flow was higher at 5 days than 1 day old at thermal neutrality (26 +/- 3 vs. 17 +/- 1 ml min-1 (100 g hindquarters)-1) and its increase in the cold was much more marked (+65 % at 5 days old vs. +25 % at 1 day old). Oxygen extraction by the hindquarters rose from 30-35 % at thermal neutrality to 65-70 % in the cold at both ages. The calculated contribution of skeletal muscle to total oxygen consumption averaged 34-40 % at thermal neutrality and 50-64 % in the cold and skeletal muscle was the major contributor to regulatory thermogenesis. Based on hindquarters glucose uptake and lactate release, carbohydrate appeared to be an important fuel for shivering. However, net uptake of fatty acids increased progressively during cold exposure at 5 days old. The enhancement in muscular blood supply and fatty acid utilization during shivering is probably related to the postnatal improvement in the thermoregulatory response of the piglet.     

Gas exchange, blood acid-base balance and mechanical muscle efficiency during incremental levels of exertion in young healthy individuals

In this study we have evaluated the changes in gas exchange variables, blood acid-base balance and the mechanical efficiency of muscle in healthy young men during an incremental exercise test. Twenty-six healthy men: age 22.1 +/- 1.4 (mean +/- SD) years, body mass 73.6 +/- 7.4 kg, height 179 +/- 8 cm, were subjects in this study. The subjects performed an incremental exercise test on a cycloergometer at a pedalling rate of 70 rev.min-1. The exercise test started at a power output of 30 W, followed by an increase of power output by 30 W every 3 minutes. Gas exchange variables were measured continuously (breath by breath). Antecubital blood samples for acid-base balance variables and plasma lactate concentration [La]pl were taken at the end of each 3-minute step. The lactate threshold (LT) in this study was defined as the highest power output above which [La]pl showed a sustained increase of > 0.5 mmol.l-1.step-1. The power output at LT amounted to 127 +/- 28 W. It corresponded to 45% of the maximal power output (MPO) reached at maximal oxygen uptake (VO2 max). The oxygen uptake at the LT amounted to 1734 +/- 282 ml.min-1 and corresponded to 48% of VO2 max (3726 +/- 363 ml.min-1). The minute ventilation at the LT amounted to 47.8 +/- 7.5 l, and its increase to the level of 125.7 +/- 19.7 l reached at the MPO was obtained mainly by intensification of breathing frequency from 23.8 +/- 3.31.min-1 to 43 +/- 5.91.min-1, for LT and MPO respectively. Analysis of the changes in PETCO2 during the incremental exercise test showed significant differences between subjects. One could recognise a group of subjects (n = 8) with high values of PETCO2 (above 45 mmHg) and a group of subjects (n = 8) with lower values of PETCO2 (below 43 mmHg). However, no significant differences in exercise tolerance, expressed by the level of MPO and maximal oxygen uptake, were found between those groups of subjects. The mechanical efficiency calculated on the basis of power output/net oxygen uptake ratio during cycling at a power output of 60 W amounted to 24.1 +/- 3.8 percent, at the LT 25.8 +/- 2.1%, whereas at the maximal power output a significant (p < 0.01) drop in muscle efficiency occurred, to the value of 23.1 +/- 1.6%. This drop in muscle efficiency occurring at the MPO may be an important factor limiting exercise tolerance when performing high power output exercise. In conclusion: The above presented data illustrate the physiological responses to incremental exercise and the level of exercise tolerance, which may serve as a reference point for the population of healthy, young physically active Polish students.     

Effects of medium-chain triglyceride ingestion on fuel metabolism and cycling performance

On three occasions separated by 10 days, six endurance-trained cyclists rode for 2 h at 60% of peak O2 uptake and then performed a simulated 40-km time trial (T-trial). During the rides, the subjects ingested a total of 2 liters of a [U-14C]glucose-labeled beverage containing a random order of either 10% glucose [carbohydrate (CHO)], 4.3% medium-chain triglycerides (MCTs); or 10% glucose + 4.3% MCTs (CHO+MCT). Although replacing CHO with MCTs slowed the T-trials from 66.8 +/- 0.4 (SE) to 72.1 +/- 0.6 min (P < 0.001), adding MCTs to CHO improved the T-trials from 66.8 +/- 0.4 to 65.1 +/- 0.5 min (P < 0.05). Faster T-trials in the CHO+MCT trial than in the CHO trial were associated with increased final circulating concentrations of free fatty acids (0.58 +/- 0.09 vs. 0.36 +/- 0.06 mmol/l; P < 0.05) and ketones (1.51 +/- 0.25 vs. 0.51 +/- 0.07 mmol/l; P < 0.01) and decreased final circulating concentrations of glucose (5.2 +/- 0.2 vs. 6.3 +/- 0.3 mmol/l; P < 0.01) and lactate (1.9 +/- 0.4 vs. 3.7 +/- 0.5 mmol/l; P < 0.05). Adding MCTs to ingested CHO reduced total CHO oxidation rates from 14 +/- 1 to 10 +/- 1 mmol/min at 2 h and from 17 +/- 1 to 14 +/- 1 mmol/min in the T-trial (P < 0.01), without affecting the corresponding approximately 5 and approximately 7 mmol/min rates of [14C]glucose oxidation. These data suggest that MCT oxidation decreased the direct and/or indirect (via lactate) oxidation of muscle glycogen. A reduced reliance on CHO oxidation at a given O2 uptake is similar to an endurance-training effect, and that may explain the improved T-trial performances.     

Prognostic value of blood lactate, base deficit, and oxygen-derived variables in an LD50 model of penetrating trauma

OBJECTIVE: To determine whether blood lactate, base deficit, or oxygen-derived hemodynamic variables correlate with morbidity and mortality rates in a clinically-relevant LD50 model of penetrating trauma. DESIGN: Prospective, controlled study. SETTING: University research laboratory. SUBJECTS: Anesthetized, mechanically-ventilated mongrel pigs (30+/-2 kg, n = 29). INTERVENTIONS: A captive bolt gun delivered a penetrating injury to the thigh, followed immediately by a 40% to 60% hemorrhage. After 1 hr, shed blood and supplemental crystalloid were administered for resuscitation. MEASUREMENTS AND MAIN RESULTS: After penetrating injury, 50.7+/-0.3% hemorrhage (range 50% to 52.5%), and a 1-hr shock period, seven of 14 animals died, compared with six of six animals after 55% to 60% hemorrhage, and 0 of nine animals after < or =47.5% hemorrhage. Only two of 13 deaths occurred during fluid resuscitation. At the LD50 hemorrhage, peak lactate concentration and base deficit were 11.2+/-0.8 mM and 9.3+/-1.5 mmol/L, respectively, and minimum mixed venous oxygen saturation, systemic oxygen delivery, and systemic oxygen consumption were 33+/-5%, 380+/-83 mL/min/kg, and 177+/-35 mL/min/kg, respectively. For comparison, baseline preinjury values were 1.6+/-0.1 mM, -6.7+/-0.6 mmol/L, 71+/-3%, 2189+/-198 mL/min/kg, and 628+/-102 mL/min/kg, respectively. Of all the variables, only lactate was significantly related to blood loss before and after fluid resuscitation in the 16 survivors. However, r2 values were relatively low (.20 to .50), which indicates that only a small fraction of the hyperiactacidemia was directly related to tissue hypoperfusion. In the whole population of survivors and nonsurvivors, both lactate and base deficit (but none of the oxygen-derived variables) correlated with blood loss. CONCLUSIONS: Arterial lactate is a stronger index of blood loss after penetrating trauma than base deficit or oxygen-derived hemodynamic variables. The reliability of arterial lactate depends on several factors, such as the time after injury, the proportion of survivors and nonsurvivors in the study population, and on factors other than tissue hypoxia.     

Inhibition of paracrine angiotensin-converting enzyme in vivo: effects on interstitial glucose and lactate concentrations in human skeletal muscle

Microdialysis was used to selectively assess the effect of the paracrine renin-angiotensin system (RAS) on interstitial glucose and lactate concentration profiles in skeletal muscle of healthy volunteers (n = 8) during basal and insulin-stimulated conditions. Paracrine RAS was selectively inhibited by local retrodialysis with enalaprilate. Under basal conditions, local administration of enalaprilate (2 micrograms mL-1) increased interstitial dialysate glucose concentration from 0.71 +/- 0.14 mmol L-1 to 0.84 +/- 0.14 mmol L-1 and decreased the serum interstitial gradient (SIGglu) compared with baseline (P < 0.02). Under clamp conditions, enalaprilate, even at the lowest concentration (0.02 microgram mL-1), increased interstitial dialysate glucose concentration from 0.77 +/- 0.11 mmol L-1 to 1.02 +/- 0.09 mmol L-1 and decreased SIGglu compared with baseline (P < 0.01). Interstitial lactate concentrations slightly increased during basal as well as during clamp conditions (P < 0.05 vs. baseline). Selective inhibition of paracrine muscle angiotensin-converting enzyme (ACE) increases interstitial glucose and lactate concentrations and decreases SIGglu in muscle by facilitating transcapillary glucose transport. This effect is more pronounced during hyperinsulinaemia and may be of clinical relevance in diabetic patients treated with therapeutic doses of enalapril.     

Effect of hyperglycemia on brain cell membrane function and energy metabolism during hypoxia-ischemia in newborn piglets

The purpose of this study was to test the hypothesis that hyperglycemia ameliorates changes in brain cell membrane function and preserves cerebral high energy phosphates during hypoxia-ischemia in newborn piglets. A total of 42 ventilated piglets were divided into 4 groups, normoglycemic/normoxic(group 1, n=9), hyperglycemic/normoxic(group 2, n=8), normoglycemic/hypoxic-ischemic(group 3, n=13) and hyperglycemic/hypoxic-ischemic(group 4, n=12) group. Cerebral hypoxia-ischemia was induced by occlusion of bilateral common carotid arteries and simultaneous breathing with 8% oxygen for 30 min. Hyperglycemia (blood glucose 350-400 mg/dl) was maintained for 90 min before and throughout hypoxia-ischemia using modified glucose clamp technique. Changes in cytochrome aa3 were continuously monitored using near infrared spectroscopy. Blood and CSF glucose and lactate were monitored. Na+, K+-ATPase activity, lipid peroxidation products (conjugated dienes), tissue high energy phosphates (ATP and phosphocreatine) levels and brain glucose and lactate levels were determined biochemically in the cerebral cortex. During hypoxia-ischemia, glucose levels in blood and CSF were significantly elevated in hyperglycemic/hypoxic-ischemic group compared with normoglycemic/hypoxic-ischemic group, but lactate levels in blood and CSF were not different between two groups. At the end of hypoxia-ischemia of group 3 and 4, triangle up Cyt aa3, Na+, K+-ATPase activity, ATP and phosphocreatine values in brain were significantly decreased compared with normoxic groups 1 and 2, but were not different between groups 3 and 4. Levels of conjugated dienes and brain lactate were significantly increased in groups 3 and 4 compared with groups 1 and 2, and were significantly elevated in group 4 than in group 3 (0.30+/-0.11 vs. 0.09+/-0.02 micromol g-1 protein, 26.4+/-7.6 vs. 13.1+/-2.6 mmol kg-1, p<0.05). These findings suggest that hyperglycemia does not reduce the changes in brain cell membrane function and does not preserve cerebral high energy phosphates during hypoxia-ischemia in newborn piglets. We speculate that hyperglycemia may be harmful during hypoxia-ischemia due to increased levels of lipid peroxidation in newborn piglet.