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PubMed2006

Changes in secretory cell turnover, and mitochondrial oxidative damage in the mouse mammary gland during a single prolonged lactation cycle suggest the possibility of accelerated cellular aging.

Milk synthesis by the mammary gland declines during prolonged lactation despite the continued suckling stimulus and complete removal of mammary secretions. Although this process has been hypothesized to result from cellular aging there has been no reported analysis of aging markers in the lactating mammary gland. The goal of these studies was to relate lactation performance in the mouse during a single prolonged lactation cycle to changes in mammary development and mitochondrial oxidative damage. During an artificially prolonged lactation cycle, the capacity of the dams to support litter growth decreased over time. This decrease was associated with decreased mammary epithelial content. Cell proliferation, along with the percentage of mammary progenitor cells, was high during early lactation, but low during prolonged lactation. Apoptosis increased during prolonged lactation. Oxidative damage to mitochondrial DNA increased during the early postpartum period and remained elevated through the end of the cycle. In contrast oxidative damage to mitochondrial protein was high during early lactation and decreased through mid lactation to increase again with prolonged lactation. The results suggest that a single prolonged lactation cycle may replicate on an accelerated basis some of the changes that occur with a lifetime of aging in organs possessing more stable cell populations.

Animals↗
PubMed1997

Serum lactates correlate with mortality after operations for complex congenital heart disease.

BACKGROUND: The objective of this study was to determine whether serum lactate levels predict mortality in children less than 1 year of age who have undergone cardiopulmonary bypass and operations for complex congenital heart disease. METHODS: The initial lactate, maximum lactate, and lactate levels at 4 to 6 hours after operation were analyzed for each of 48 children less than 12 months of age who underwent cardiopulmonary bypass. RESULTS: Data were analyzed for the 6 patients who died and the 42 patients who survived. For the patients who died, the initial postoperative serum lactate, maximum lactate, and 4- to 6-hour lactate levels were significantly higher than those in the patients who survived. All patients with an initial lactate less than 7 mmol/L, a maximum lactate less than 9 mmol/L, or a 4- to 6-hour lactate level less than 4 mmol/L survived to hospital discharge. CONCLUSIONS: Serum lactate levels may be a useful predictor of mortality in children less than 1 year of age who have undergone cardiopulmonary bypass. An elevation in serum lactate level after a complex operation for congenital heart disease should be taken as a serious indicator of potential mortality.

Age Factors↗
PubMed1999

Elevated leptin concentrations in pregnancy and lactation: possible role as a modulator of substrate utilization.

Energy needs are increased during pregnancy and lactation. These increased energy needs may be met through partitioning of nutrients for energy utilization which is under hormonal control. The objective of the present studies was to determine if changes in plasma leptin occurred during pregnancy and lactation and if the changes were related to prolactin. Plasma leptin and prolactin were measured longitudinally in 9 women through pregnancy and lactation. In a second study, leptin and prolactin were measured 4 days and 28 days postpartum in 21 lactating women. Mean plasma leptin during the three trimesters of pregnancy was significantly higher (29.3+/-2.8 ng/ml) when compared to mean leptin during the three time periods of lactation (19.3+/-3.2 ng/ml) and control groups (9.8+/-1.4 ng/ml). Plasma leptin was elevated early in pregnancy and remained elevated throughout pregnancy. In the second study, the mean plasma leptin in the lactating women was significantly higher 4 days postpartum (17.3+/-3.7 ng/ml) and 28 days postpartum (19.2+/-3.9 ng/ml) when compared to controls (11.6+/-1.2 ng/ml). Prolactin in the control subjects (24+/-4 ng/ml) was significantly lower than in the pregnant (202+/-16 ng/ml) and lactating (108+/-26 ng/ml) groups. Similar observations were made in the second study (controls 20+/-2 ng/ml; lactation 28 days 159+/-21 ng/ml). Leptin during lactation was lower than in pregnancy but higher than control subjects. Regression analysis suggested that BMI and prolactin can be used as predictors of leptin in pregnancy and lactation. The increase in leptin and prolactin early in pregnancy suggests an association between the two hormones. Results of the present studies and research done by other investigators presents a strong role for leptin during pregnancy and lactation. Leptin is regulated by factors other than adiposity especially in reproductive women leading to our hypothesis that there are leptin and prolactin mediated effects on substrates used for energy utilization during pregnancy and lactation.

Adolescent↗
PubMed2001

Non-metabolic and metabolic factors causing lactational anestrus: rat models uncovering the neuroendocrine mechanism underlying the suckling-induced changes in the mother.

Follicular development and ovulation are strongly inhibited during lactation. Administration of a high dose of estrogen induces luteinizing hormone (LH) surges in ovariectomized lactating rats, suggesting that brain mechanisms regulating cyclic LH release remain intact in lactating mothers. On the other hand, tonic LH release is profoundly suppressed in lactating rats. This suggests that lactational anestrus is mainly due to suppression of the mechanism regulating pulsatile gonadotropin-releasing hormone secretion in the hypothalamus, which is responsible for follicular development and steroid production. Both metabolic and non-metabolic factors are involved in suppressing pulsatile LH secretion throughout lactation in rats. During the first half of lactation, pulsatile LH secretion is strongly suppressed, even if milk production is attenuated by pharmacological blockade of prolactin secretion in ovariectomized lactating rats. Pulsatile LH release quickly recovers by removing pups or blocking neuronal input by hypothalamic deafferentation during the period. These data suggest that the suckling stimulus itself is responsible for suppression of LH release during the first half of lactation. During the second half of lactation, negative energy balance, which is caused by the milk production, appears to play a dominant role in suppressing LH secretion. Blockade of milk production by inhibiting prolactin release causes a gradual increase in LH release even if the vigorous suckling stimulus by foster pups remains. In conclusion, the suckling stimulus itself predominantly suppresses LH pulses during the first half of lactation and metabolic factors take over the role of the suckling stimulus during the second half of lactation.

Anestrus↗
PubMed1997

Substrate and cofactor specificity and selective inhibition of lactate dehydrogenase from the malarial parasite P. falciparum.

Lactate dehydrogenase from the malarial parasite Plasmodium falciparum has many amino acid residues that are unique compared to any other known lactate dehydrogenase. This includes residues that define the substrate and cofactor binding sites. Nevertheless, parasite lactate dehydrogenase exhibits high specificity for pyruvic acid, even more restricted than the specificity of human lactate dehydrogenases M4 and H4. Parasite lactate dehydrogenase exhibits high catalytic efficiency in the reduction of pyruvate, kcat/Km = 9.0 x 10(8) min(-1) M(-1). Parasite lactate dehydrogenase also exhibits similar cofactor specificity to the human isoforms in the oxidation of L-lactate with NAD+ and with a series of NAD+ analogs, suggesting a similar cofactor binding environment in spite of the numerous amino acid differences. Parasite lactate dehydrogenase exhibits an enhanced kcat with the analog 3-acetylpyridine adenine dinucleotide (APAD+) whereas the human isoforms exhibit a lower kcat. This differential response to APAD+ provides the kinetic basis for the enzyme-based detection of malarial parasites. A series of inhibitors structurally related to the natural product gossypol were shown to be competitive inhibitors of the binding of NADH. Slight changes in structure produced marked changes in selectivity of inhibition of lactate dehydrogenase. 7-p-Trifluoromethylbenzyl-8-deoxyhemigossylic acid inhibited parasite lactate dehydrogenase, Ki = 0.2 microM, which was 65- and 400-fold tighter binding compared to the M4 and H4 isoforms of human lactate dehydrogenase. The results suggest that the cofactor site of parasite lactate dehydrogenase may be a potential target for structure-based drug design.

Allosteric Regulation↗
PubMed1979

Relationship between lactate and glutamine metabolism in vitro by the kidney: differences between dog and rat and importance of alanine synthesis in the dog.

Interaction between lactate (1 or 5 mM) and glutamine (1 or 5 mM) metabolism was studied with renal cortical slices incubated at a pH of 7.0 and obtained from acidotic (ammonium chloride) dogs and rats. The effect of aminooxyacetate (0.2 mM), dichloroacetate (3 mM), and fluoroacetate (0.05 mM) was also studied. Significant differences were observed between dog and rat. In the dog, lactate had no effect on glutamine uptake and vice versa, but gluconeogenesis increased. Ammonia production, however, decreased by 13 to 21%, whereas a significant increase in alanine production was noted. In the rat, glutamine extraction and ammonia production dropped by 33% with 5 mM lactate. In contrast to the observation in the dog, no production of alanine was noted, but significant accumulation of glutamate took place. Amino-oxyacetate inhibited alanine production in the dog and reestablished ammoniagenesis, and it led to a marked decrement in the uptake of lactate and glucose production in both species. Dichloroacetate in the dog resulted in a reduction in pyruvate, alanine, glucose, and ammonia production while glutamate accumulation was observed. In both species, fluoroacetate stimulated glutamine uptake and ammonia production. With lactate alone, fluoroacetate decreased lactate uptake and glucose production. With both lactate and glutamine in the medium, fluoroacetate prevented any effect of lactate on ammoniagenesis. The present study demonstrates that lactate has a modest depressing effect on renal ammonia production by dog slices through increased synthesis of alanine and redistribution of nitrogen from glutamine. In the rat, the depressing effect of lactate on ammonia production in the alanine amino-transferase deficient kidney occurs through accumulation of glutamate. The data also reveal that oxidation of lactate to carbon dioxide is greater in the dog than it is in the rat, but that gluconeogenesis from lactate is more important in the rat.

Acidosis↗
PubMed1991

Carrier-mediated L-lactate transport in brush-border membrane vesicles from rat placenta during late gestation.

The mechanism for L-lactate transport across microvillous membrane vesicles prepared from rat placenta was examined. Uptake of L-lactate into these vesicles was mainly the result of transport into the intravesicular (osmotically active) space. The initial rate of L-lactate uptake was not affected by the presence of an inward gradient of either Na+ or K+. In the presence of an inward-directed proton gradient, L-lactate uptake was markedly stimulated, accumulating at concentrations 6-7-fold higher than the equilibrium. Lower transmembrane pH gradients were associated with slower initial uptakes and smaller overshoots. L-Lactate uptake determined under an inside-directed pH gradient was strongly inhibited by p-chloromercuriphenylsulphonic acid, a protein-thiol oxidizing agent. L-Lactate uptake was: (1) saturable as a function of the concentration of L-lactate, (2) inhibited by monocarboxylic acids such as pyruvate, D-lactate, beta-hydroxybutyrate and alpha-cyano-4-hydroxycinnamic acid, and (3) temperature-dependent. When present inside the vesicles, L-lactate, pyruvate and beta-hydroxybutyrate caused trans-stimulation of L-lactate uptake both in the presence and in the absence of an inside-directed pH gradient, indicating that L-lactate transport is a reversible process that can be shared by other monocarboxylic acids. There were no significant changes in maximal initial rate or in the kinetic parameters of L-lactate transport during the last 3 days of gestation.

4-Chloromercuribenzenesulfonate↗
PubMed2001

Increased colocalization of corticotropin-releasing factor and arginine vasopressin in paraventricular neurones of the hypothalamus in lactating rats: evidence from immunotargeted lesions and immunohistochemistry.

In lactating female rats, tonically elevated glucocorticoid secretion is accompanied by blunted stress responsiveness, reduced expression of hypothalamic corticotropin-releasing factor (CRF) mRNA and modest increases in arginine vasopressin (AVP) expression in the paraventricular nucleus (PVN). To determine the relative contribution of CRF and AVP to parvocellular function, we performed selective CRF (CRF-Tx) or AVP (AVP-Tx) lesions in the PVN neurones of ovariectomized virgin or lactating females (day 2 of lactation) by using ricin A associated with monoclonal antibodies directed towards CRF or AVP. We also performed double immunohistochemical labelling of CRF and AVP in the PVN of control rats injected with immunoglobulin (Ig)Gs associated with the ricin A (IgG-Tx). Brains were collected 12 days after the lesion and processed for in situ hybridization of CRF and AVP mRNA or for double fluorescence CRF and AVP immunohistochemistry. We found that lactating females exhibit a high degree of CRF and AVP colocalization in parvocellular PVN neurones, hypothalamic processes and median eminence terminals compared to virgins. While CRF mRNA is significantly reduced in lactating rats, AVP mRNA and protein levels are greatly enhanced in parvocellular PVN neurones during lactation. Hypothalamic CRF or AVP ricin-A lesions significantly reduced both CRF and AVP expression (15-35% decrease) as well as peptide immunoreactivity in PVN neurones in both groups of females. The specificity of the lesions varied between virgins and lactators since in virgin females, AVP-Tx did not affect CRF mRNA expression whereas in lactating females, this same lesion significantly reduced CRF mRNA expression, suggesting that parvocellular PVN neurones are more sensitive to the effects of the lesions during lactation. In both virgins and lactators, lesion with CRF-Tx tended to increase AVP mRNA expression; however, in virgins, parvocellular PVN neurones were possibly compensating for the loss of CRF synthesis by increasing AVP expression and immunoreactivity. We conclude that lactation is associated with a high degree of CRF and AVP colocalization in parvoPVN neurones and that the increased AVP production in these neurones increases their sensitivity to immunotargeted lesions. The opposite regulation of CRF and AVP gene expression during lactation might provide a useful model to study differential sensitivity to glucocorticoid feedback or hypothalamic activation of transcription factors.

Animals↗
PubMed1994

Direct measurement of extracellular lactate in the human hippocampus during spontaneous seizures.

The effect of clinical, spontaneous-onset seizures on extracellular fluid lactate was investigated by the method of lactography, the in vivo on-line measurement of lactate levels using microdialysis. Studies of experimental animals have suggested that generation of extracellular lactate as measured by microdialysis is an index of local glucose utilization and is dependent on the activity of neurons under physiological conditions. Patients with medically refractory complex partial epilepsy underwent stereotactic implantation of combination depth electrode/microdialysis probes into both hippocampi for 7-16 days. During spontaneous complex partial seizures with secondary generalization, extracellular lactate levels rose by 91 +/- 32%. Moreover, this increase persisted for 60-90 min. During a unilateral hippocampal seizure that did not propagate to the contralateral hippocampus, the increase in lactate content was restricted to the side of seizure activity. Between seizures, extracellular lactate levels correlated with the frequency of interictal spikes. In summary, these data suggest that brief clinical seizures increase nonoxidative glucose metabolism significantly as measured by the generation of extracellular lactate. Furthermore, the increase in extracellular lactate levels is limited to the site of seizure activity. Lactate is transported extracellularly via a lactate/proton cotransporter, therefore, the rise in extracellular lactate level may mediate the drop in pH0 associated with seizure activity. As acidification of the extracellular compartment has an inhibitory effect on neuronal excitability, the rise in extracellular lactate content may be a mechanism of seizure arrest and postictal refractoriness. Moreover, extracellular lactate may also mediate the decreased seizure susceptibility associated with frequent interictal spikes.

Adolescent↗
PubMed2000

Lactate concentration in plasma and red blood cells during incremental exercise.

The purpose of this study was to investigate the distribution of lactate in plasma and red blood cells (RBC) in capillary blood during and after incremental exercise. We measured capillary plasma lactate and whole blood lactate of 10 subjects during incremental treadmill running and the first 20 min of recovery. To minimize lactate exchange from plasma to RBC between sampling and analysis, a recently developed rapid plasma separation method was used. RBC lactate was calculated. The RBC/plasma lactate concentration ratio decreased from 1.0 (0.85-1.28) before to 0.37 (0.25-0.45) after exhaustive exercise (plasma lactate 15.9 (12.2-19.5)mmol x I(-1), RBC lactate 4.8 (4.0-7.0) mmol x 1(-1)), thus showing that capillary plasma lactate increased much more rapidly than intracellular lactate during incremental exercise. In the first 5 minutes of recovery intracellular lactate still rose while plasma lactate already declined. Then both decreased while the concentration ratio as well as the absolute concentration gradient remained nearly constant (ratio 20 min after exercise termination: 0.43 (0.19-0.54).

Adolescent↗
PubMed1997

The plasma lactate response to exercise and endurance performance: relationships in elite triathletes.

The lactate response to exercise has been studied thoroughly during the last decades and it has been described using a variety of terms and definitions. Numerous investigations observed close relationships between the lactate response and endurance performance. The main question in this study was which of the various lactate responses during incremental exercise described in the literature was the best indicator of endurance performance. The plasma lactate response (PLR) was assessed during an incremental exercise test on 13 male elite triathletes (age 25.5+/-5.8 yrs; HT 179.7+/-5.4 cm; WT 71.3+/-4.7 kg) on a bicycle ergometer. The load was started at 2.5 W/kg and increased by 40 W every 4 min. We evaluated the following PLR-parameters: the workloads at the fixed lactate levels of 2, 3, 4, 5, 6, 7, and 8 mmol/l which were assessed by extrapolation from a workload-lactate-heart rate curve (P2, P3, P4, P5, P6, P7, P8 respectively), the lactate threshold which was defined as the workload at the point at which a non-linear increase of blood lactate occurred (Plt), and the workload at the lactate level that was 1 mmol/l above the baseline (P + 1). Four to seven weeks after the laboratory test, heart rate and lactate levels were assessed during a 40-km long time trial on a bicycle. Two parameters were considered as indicative of athletic performance: the road racing time (Tt), and the workload extrapolated from the workload-lactate-heart rate curve at the heart rate and lactate levels observed during the time trial (Pt). Only P2 showed a significant correlation with Tt (r=-0.65; p < 0.05; se = 72.5 s). Multiple regression analysis with the anthropometric parameters height and weight as additional independent parameters did not change the predictive value. We concluded that for predicting the cycling performance of similarly well-trained subjects the predictive value of PLR is negligible.

Adult↗
PubMed1982

Acetate metabolism in lactating sheep.

1. The metabolism of acetate, glucose and D(-)-3-hydroxybutyrate was studied in lactating and non-lactating sheep in vivo. Special consideration was given to the utilization by hind-limb muscle in both groups of sheep and the uptake of nutrients by the lactating mammary gland was also measured. 2. The entry of acetate into the circulation (mmol/h per kg body-weight) was similar in all experimental animals at a given arterial concentration of acetate. However, normal lactation was associated with a reduced extraction of acetate by muscle and the 'spared' acetate was comparable with that removed by the udder. Feeding lactating ewes a 700 g concentrate/kg ration tended to prevent this redistribution of acetate utilization. 3. The muscles of non-lactating ewes utilized sufficient glucose, when corrected for lactate release, to account for 57% of the oxygen utilization by muscle. In lactation this fell to 32% largely because of an increased lactate production. D(-)-3-Hydroxybutyrate utilization by muscle accounted for 16-17% of the O2 consumed by the muscle in non-lactating and lactating sheep. 4. Lactating mammary gland metabolism in sheep was similar to published values for dairy cows and goats. Thus the extraction (%) of glucose, O2, acetate and D(-)-3-hydroxybutyrate was 25, 28, 62 and 53 respectively. Blood flow was 529 ml/min per kg udder and the ratio, blood flow: milk flow was 475. glucose used by the udder relative to the whole animal utilization rate may be less in sheep than in cows and goats, but the comparable proportion for acetate is as large or larger than in these species.

3-Hydroxybutyric Acid↗
PubMed1994

Maternal protein reserves and their influence on lactational performance in rats. 4. Tissue protein synthesis and turnover associated with mobilization of maternal protein.

The present study was undertaken to investigate the changes in muscle protein turnover involved in the rapid mobilization of protein in rats subjected to severe protein restriction during lactation. Estimates of mammary gland and liver protein synthesis were also made during lactation. Multiparous female Sprague-Dawley rats, caged individually following mating, were offered a high-protein diet (H; 215 g crude protein (N x 6.25; CP)/kg dry matter (DM)) ad lib. until parturition. Following parturition, half the females continued to receive diet H, whilst the remainder were offered a diet low in protein (L; 90 g CP/kg DM) ad lib. On days 2, 4, 8 and 12 of lactation, groups of females were used in the estimation of tissue protein synthesis (flooding dose of [3H]phenylalanine) immediately after a milk sample had been obtained. Rates of muscle protein synthesis were unchanged during lactation in group H. The feeding of diet L during lactation reduced the muscle protein synthesis on day 12 to rates that were lower than group H and also the rate on diet L on day 2 (P < 0.01). However, this fall in muscle protein synthesis was not rapid and muscle fractional synthesis rate (FSR) was different from group H only from day 8 (P < 0.05). Estimated rates of mammary protein synthesis appeared to be generally unchanged by dietary treatment or stage of lactation. Liver FSR was also unchanged by dietary protein supply or stage of lactation. The effect of dietary protein restriction on liver size and protein content during lactation influenced liver absolute synthesis rate (ASR), and on days 8 and 12 of lactation liver ASR was lower in group L than in group H (P < 0.001). The loss of muscle protein in rats fed on diet L during lactation (133 mg) occurred mainly between days 2 and 8 of lactation and was primarily associated with a dramatic increase in degradation (13.0% per d), with the decline in synthesis having a much smaller role. A decline in muscle protein degradation during the latter half of lactation was part of the mechanism that prevented excessive muscle protein catabolism. It is thought that the estimation of mammary protein synthesis in the present study was impaired by the milk sampling procedure previously used.

Animals↗
PubMed1982

Pulsatile administration of gonadotropin releasing hormone to lactating sows: endocrine changes associated with induction of fertile estrus.

Two experiments were conducted to determine whether pulsatile administration of gonadotropin releasing hormone (GnRH) would induce estrus and ovulation in lactating, anestrous sows. In each experiment, six lactating sows received GnRH, i.v. (2.5 micrograms every 2 h, Exp. 1; 1.5 micrograms every h, Exp. 2) until 24 h after estrus or 7 days, whichever came first. In Experiment 1, three of six GnRH-treated lactating sows exhibited estrus 4.0 +/- 0.0 days after GnRH treatment began. All three GnRH-treated sows conceived at the estrus induced during lactation. Patterns of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in serum around estrus were similar between GnRH-treated sows that exhibited estrus during lactation and weaned control sows. However, in GnRH-treated sows that did not show estrus, a preovulatory-like surge in FSH, but not in LH, occurred on Day 4 of GnRH treatment. Prolactin concentrations in serum dropped from 25.6 +/- 2.4 ng/ml during lactation to less than 6 ng/ml within 12 h after weaning (Exp. 1). In Experiment 2, all six GnRH-treated sows exhibited estrus 3.8 +/- 0.3 days after initiation of GnRH treatment, and five sows conceived. Patterns of LH and FSH during lactation were similar between GnRH-treated and lactating control sows during the first 3 days of GnRH treatment. During 3 days before estrus, LH concentrations were lower (P less than 0.05) and FSH concentrations tended to be higher (P less than 0.20) in lactating GnRH-treated sows than in control sows whose litters had been weaned. Concentrations of estradiol in GnRH-treated sows were greater than those in controls during lactation but were similar in both groups on the day of estrus. In both experiments, concentrations of progesterone were greater in GnRH-treated than in control sows prior to and during estrus. We conclude that, despite some differences in hormone secretion between GnRH-treated lactating sows and sows with litters weaned, pulsatile administration of GnRH caused requisite endocrine changes for fertile estrus during lactation.

Animals↗
PubMed1987

Detection of relaxin by immunohistochemistry in the corpus luteum during lactation.

The occurrence of relaxin in corpora lutea (CL) throughout lactation was studied in rats and pigs using the avidin-biotin immunoperoxidase procedure and homologous antisera to purified relaxins. In the rat, both CL from the previous pregnancy (CLp) and CL formed after postpartum ovulation, termed CL of lactation (CLL), were studied. In the rat, relaxin was localized only in cells of the CLp in early lactation, and immunostaining declined with advancing lactation. In late lactation (Days 16-20), immunoreactive relaxin first appeared in cells of the CLL, although the intensity was less relative to that observed in the CLp in early lactation. Cells of the CLp were sensitive to the effects of exogenous prostaglandins (PG) as shown by a loss of relaxin immunostaining at both 12 and 48 h after a PGF2 alpha challenge. In the sow, the CLp showed highest immunostaining in early lactation with a gradual reduction as lactation progressed, such that by Day 20 lactation, immunostaining was lost. These localization studies show that immunoreactive relaxin is present in the CL during lactation. Low levels of relaxin localized in the CLL of late lactation in the rat probably represents newly formed hormone, whereas the immunostaining in the CLp of the pig and rat appears to be residual relaxin and an indicator of the degeneration of the CLp with advancing lactation.

Animals↗
PubMed2000

Lactate regulates pyruvate uptake and metabolism in the preimplantation mouse embryo.

This study was an investigation of the interaction of lactate on pyruvate and glucose metabolism in the early mouse embryo. Pyruvate uptake and metabolism by mouse embryos were significantly affected by increasing the lactate concentration in the culture medium. In contrast, glucose uptake was not affected by lactate in the culture medium. At the zygote stage, the percentage of pyruvate taken up and oxidized was significantly reduced in the presence of increasing lactate, while at the blastocyst stage, increasing the lactate concentration increased the percentage of pyruvate oxidized. Lactate oxidation was determined to be 3-fold higher (when lactate was present at 20 mM) at the blastocyst stage compared to the zygote. Analysis of the kinetics of lactate dehydrogenase (LDH) determined that while the V(max) of LDH was higher at the zygote stage, the K(m) of LDH was identical for both stages of development, confirming that the LDH isozyme was the same. Furthermore, the activity of LDH isolated from both stages was reduced by 40% in the presence of 20 mM lactate. The observed differences in lactate metabolism between the zygote and blastocyst must therefore be attributed to in situ regulation of LDH. Activity of isolated LDH was found to be affected by nicotinamide adenine dinucleotide(+) (NAD(+)) concentration. In the presence of increasing concentrations of lactate, zygotes exhibited an increase in autofluorescence consistent with a depletion of NAD(+) in the cytosol. No increase was observed for later-stage embryos. Therefore it is proposed that the differences in pyruvate and lactate metabolism at the different stages of development are due to differences in the in situ regulation of LDH by cytosolic redox potential.

Animals↗
PubMed1995

Combined measurements of blood lactate concentrations and gastric intramucosal pH in patients with severe sepsis.

OBJECTIVE: To compare the prognostic value of blood lactate concentrations, gastric intramucosal pH, and their combination in patients with severe sepsis. DESIGN: Prospective, noninterventional study. SETTING: Medical/surgical intensive care unit of a university hospital. PATIENTS: The study included 35 consecutive patients (44 to 82 yrs) with severe sepsis as defined by fever or hypothermia (rectal temperature > 38.3 degrees or < 35.5 degrees C), tachycardia (heart rate > 100 beats/min), tachypnea (respiratory rate > 20 breaths/min) or mechanical ventilation, abnormal white blood cell count (> 10 or < 6 x 10(3) cells/mm3), hypotension (systolic arterial pressure < 90 mm Hg), and evidence of organ dysfunction (oliguria or deterioration of mental status). INTERVENTIONS: Arterial lactate concentration and intramucosal pH were measured at the time of study entry, and at 4 and 24 hrs later. Hemodynamic data and oxygen-derived variables were determined at the time of study entry and 24 hrs later. Arterial blood and balloon saline gases were also determined to obtain the pH gap (arterial pH-intramucosal pH) and the PCO2 gap (intramural PCO2-PaCO2). MEASUREMENTS AND MAIN RESULTS: Of the 35 patients, 19 survived the intensive care unit stay. At the time of study admission, 23 (66%) patients had an increased lactate concentration (> 2 mEq/L) and 26 (74%) had a low intramucosal pH (< 7.32). Initially, there were no significant differences in blood lactate concentrations between nonsurvivors and survivors (3.2 +/- 1.5 vs. 2.8 +/- 2.3 mEq/L). Lactate concentrations remained high in nonsurvivors and progressively decreased in survivors (4 hrs: 3.3 +/- 1.1 mEq/L in nonsurvivors vs. 2.2 +/- 0.9 mEq/L in survivors [p < .01]; 24 hrs: 3.5 +/- 2.0 mEq/L in nonsurvivors vs. 1.9 +/- 1.1 mEq/L in survivors [p < .05]). Intramucosal pH was lower in the nonsurvivors than in the survivors initially (7.19 +/- 0.15 in nonsurvivors vs. 7.30 +/- 0.14 in survivors [p < .05]), at 4 hrs (7.18 +/- 0.17 in nonsurvivors vs. 7.29 +/- 0.13 in survivors [p = .06]), and at 24 hrs (7.19 +/- 0.31 in nonsurvivors vs. 7.30 +/- 0.17 in survivors [p < .05]). Of the 23 patients with initially high lactate concentrations, 12 (60%) of the 20 patients with low intramucosal pH died, as compared with one (33%) of the three patients with normal intramucosal pH (p = .052). Of the 14 patients with persistently high lactate concentrations at 24 hrs, all nine (100%) patients with low intramucosal pH, but only two (40%) of five patients with normal intramucosal pH died (p < .001). No significant relationship was found between lactate or intramucosal pH and oxygen-derived variables. Intramucosal pH correlated better with gastric intramural PCO2 (r2 = .58) than with arterial bicarbonate or base deficit/excess. Intramural PCO2 was a more specific predictor of mortality than intramucosal pH. When compared with patients with normal lactate concentrations, those patients with high lactate concentrations had a higher pH gap (0.22 +/- 0.22 vs. 0.07 +/- 0.13 [p < .01]) and PCO2 gap [21.0 +/- 33.9 vs. 1.8 +/- 9.8 torr [2.79 +/- 4.5 vs. 0.24 +/- 1.34 kPa]; p < .01). CONCLUSIONS: Both lactate concentrations and intramucosal pH represent reliable prognostic indicators in severe sepsis, and their combination improves the prognostic assessment in these patients. Both variables are better prognostic indicators than oxygen-derived variables. Intramural PCO2 appears to be a more specific variable than intramucosal pH, which partially reflects systemic metabolic acidosis. Combined determinations of blood lactate concentrations and intramucosal pH or intramural PCO2 may help to predict outcome from severe sepsis.

APACHE↗
PubMed1978

Effect of glucose infusion on glucose and lactate metabolism in normal and burned guinea pigs.

We have used the simultaneous primed-constant infusion of 6-3H-glucose and U-14C-lactate to investigate the effect of an exogenous glucose infusion (55 mumole/kg.min) on glucose and lactate metabolism in normal and burned guinea pigs. Before the unlabeled glucose infusion, glucose turnover was higher in the burned animals than in the controls, but lactate turnover was similar. During the unlabeled glucose infusion, lactate production increased in both control (73%) and burned animals (104%), yet arterial lactate concentration did not rise in either group. The ability of tissue uptake of lactate to keep pace with increased lactate production appeared to be related to an enhancement of lactate oxidation. When a two-pool model was used to calculate glucose-lactate interrelationships, it was concluded that during the glucose infusion Cori cycle flux (glucose to lactate to glucose) was higher in burned animals than in controls. Also, the primary route of oxidation of infused glucose in controls and particularly in burned animals appeared to be through conversion to lactate and subsequent oxidation of lactate.

Animals↗