Responses in whole-body amino acid kinetics to an acute, sub-clinical endotoxin challenge in lambs

AbstractSome effects of parasitism, endotoxaemia or sepsis can be mitigated by provision of extra protein. Supplemented protein may encompass a metabolic requirement for specific amino acids (AA). The current study investigates a method to identify and quantify the amounts of AA required during inflammation induced by an endotoxin challenge. One of each pair of six twin sheep was infused in the jugular vein for 20 h with either saline (control) or lipopolysaccharide (LPS, 2 ng/kg body weight per min) fromEscherichia coli. Between 12 and 20 h a mixture of stable isotope-labelled AA was infused to measure irreversible loss rates. From 16 to 20 h all sheep were supplemented with a mixture of unlabelled AA infused intravenously. Blood samples were taken before the start of infusions, and then continuously over intervals between 14 and 20 h. At 20 h the sheep were euthanised, and liver and kidney samples were taken for measurement of serine-threonine dehydratase (SDH) activity. LPS infusion decreased plasma concentrations of most AA (P<0·05;P<0·10 for leucine and tryptophan), except for phenylalanine (which increasedP=0·022) and tyrosine. On the basis of the incremental response to the supplemental AA, arginine, aspartate, cysteine, glutamate, lysine (tendency only), glycine, methionine, proline, serine and threonine were important in the metabolic response to the endotoxaemia. The AA infusion between 16 and 20 h restored the plasma concentrations in the LPS-treated sheep for the majority of AA, except for glutamine, isoleucine, methionine, serine and valine. LPS treatment increased (P<0·02) SDH activity in both liver and kidney. The approach allows quantification of key AA required during challenge situations.

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Effects of continuous intravenous infusion of an ovine placental extract enriched in placental lactogen on plasma hormones, metabolites and metabolite biokinetics in non-pregnant sheep

Journal of Endocrinology ◽

10.1677/joe.0.1130277 ◽

1987 ◽

Vol 113 (2) ◽

pp. 277-283 ◽

Cited By ~ 20

Author(s):

G. Thordarson ◽

G. H. McDowell ◽

S. V. Smith ◽

S. Iley ◽

I. A. Forsyth

Keyword(s):

Jugular Vein ◽

Control Period ◽

Plasma Concentrations ◽

Placental Lactogen ◽

Saline Control ◽

Irreversible Loss ◽

Esterified Fatty Acids ◽

Pregnant Sheep ◽

Plasma Hormones ◽

Placental Extract

ABSTRACT Continuous intravenous infusions of saline or of a placental extract containing ovine placental lactogen were given to three non-pregnant, non-lactating ewes over periods of 36 h, 1 week apart. During saline infusion no placental lactogen was detected in jugular vein plasma, but infusion of the placental extract raised the placental lactogen concentration from undetectable to 40-50 μg/l, similar to concentrations in ewes with one fetus on day 90 of pregnancy. By comparison with the saline control period, infusion of the placental extract consistently increased both plasma concentrations and irreversible loss of non-esterified fatty acids. Plasma concentrations of glucose and urea, but not irreversible loss of these metabolites, were consistently increased. Although the placental extract was not subjected to extensive purification, it was enriched in placental lactogen and contained no detectable contamination with insulin, prolactin or growth hormone. The results are suggestive of a role for placental lactogen in modifying metabolism and acting during pregnancy to provide nutrients for fetal metabolism. J. Endocr. (1987) 113, 277–283

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Ventromedial hypothalamic lesions impair glucoregulation in response to endotoxin

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1997.272.5.r1525 ◽

1997 ◽

Vol 272 (5) ◽

pp. R1525-R1531 ◽

Cited By ~ 2

Author(s):

J. P. Lynch ◽

M. M. Wojnar ◽

C. H. Lang

Keyword(s):

Metabolic Response ◽

Plasma Concentrations ◽

Ventromedial Hypothalamus ◽

Whole Body ◽

Tnf Alpha ◽

Hormone Release ◽

Glucose Flux ◽

Bilateral Lesions ◽

Stimulation Of

The purpose of the present study was to determine the role of the ventromedial hypothalamus (VMH) in regulating counter-regulatory hormone release and the increase in glucose flux that is observed after injection of endotoxin [lipopolysaccharide (LPS)]. Bilateral lesions of the VMH were produced electrolytically 2 wk before the experiment; sham-operated rats served as controls. [3-3H]glucose was infused to assess whole body glucose flux before and for 4 h after intravenous injection of Escherichia coli LPS. In control rats, LPS increased the plasma concentrations of glucose and lactate and the rates of glucose appearance and disappearance. In these animals, LPS also produced sustained elevations in corticosterone, glucagon, and catecholamines. In contrast, the glucose metabolic response to LPS was attenuated by > 50% in VMH-lesioned rats. These changes were associated with a blunted increase in the plasma concentration of glucagon, epinephrine, and norepinephrine in VMH-lesioned rats compared with control animals. There was no difference in the plasma concentrations of corticosterone or TNF-alpha between the two groups after LPS or the responsiveness of sham- and VMH-lesioned rats to an infusion of either glucagon or epinephrine. These data indicate that the VMH plays a central role in regulating the secretion of glucagon and catecholamines and the stimulation of glucose flux after LPS.

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Epinephrine-induced changes in hepatic glucose production after ethanol

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1994.266.6.e863 ◽

1994 ◽

Vol 266 (6) ◽

pp. E863-E869

Author(s):

C. H. Lang ◽

P. E. Molina ◽

N. Skrepnick ◽

G. J. Bagby ◽

J. J. Spitzer

Keyword(s):

Glucose Metabolism ◽

Metabolic Response ◽

Hepatic Glucose Production ◽

Plasma Concentrations ◽

Plasma Catecholamines ◽

Glucose Production ◽

Whole Body ◽

Metabolic Clearance ◽

Hepatic Glucose ◽

Acute Ethanol

Previous studies indicate that catecholamines play an important role in mediating the glucose metabolic response to endotoxin. Because acute ethanol (EtOH) intoxication impairs this response, the present study was initiated to ascertain whether EtOH attenuates the lipopolysaccharide response by decreasing the increment in plasma catecholamines after endotoxin or by decreasing the responsiveness of rats to epinephrine. All studies were performed on chronically catheterized fasted rats infused intravenously with either EtOH or an equal volume of saline. In the first series of experiments, intravenous administration of Escherichia coli endotoxin increased, to the same extent, the plasma concentrations of epinephrine and norepinephrine in both saline- and EtOH-infused rats. In the second study, rats were infused with [3-3H]glucose to assess whole body glucose metabolism and the ability of EtOH to alter the glucose metabolic response to epinephrine. The exogenous infusion of a maximally stimulating dose of epinephrine (1 microgram.min-1.kg-1) into saline-infused control animals for 3 h produced a marked hyperglycemia that resulted from a sustained increase in the rate of hepatic glucose production and a reduction in the metabolic clearance rate for glucose. EtOH infusion did not prevent the epinephrine-induced hyperglycemia but blunted the stimulatory effect of epinephrine on glucose production. The differences in glucose metabolism between saline- and EtOH-treated rats could not be explained by changes in plasma insulin or glucagon concentrations. Furthermore, the ability of EtOH to impair the epinephrine-induced increase in glucose production was still evident in rats treated with 4-methylpyrazole, an inhibitor of alcohol dehydrogenase.(ABSTRACT TRUNCATED AT 250 WORDS)

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Sarcosine kinetics in pigs by infusion of [1-14C]sarcosine: use for refining estimates of glycine and threonine kinetics

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1991.260.4.e662 ◽

1991 ◽

Vol 260 (4) ◽

pp. E662-E668 ◽

Cited By ~ 1

Author(s):

O. Ballevre ◽

V. Buchan ◽

W. D. Rees ◽

M. F. Fuller ◽

P. J. Garlick

Keyword(s):

Production Rate ◽

Hippuric Acid ◽

Mean Value ◽

Whole Body ◽

Irreversible Loss ◽

True Value ◽

Pool Model ◽

Liver And Kidney ◽

Direct Loss

To investigate in vivo the interconversion between glycine (Gly) and its N-methyl product sarcosine (Sar), [1-13C]Gly and [1-14C]Sar were infused into hourly fed pigs receiving diets with low- and high-threonine levels. An open two-pool model was developed to calculate Sar demethylation (DM) and Gly methylation (GM). During [1-14C]Sar infusion, intracellular Gly specific radioactivities (SA) in the liver and kidney were higher than plasma Gly SA, suggesting that demethylation of Sar occurred in those tissues. DM estimated by using hippuric acid (HA) as the production pool had a mean value of 1.55 mumol.kg-1.h-1, similar to the Sar production rate (mean 1.85 mumol.kg-1.h-1). GM was undetectable (less than 0.5 mumol.kg-1.h-1). These results suggest that, in fed pigs, Sar is produced mainly from choline catabolism and is degraded only to Gly in liver and kidney. On the assumption that Sar degradation gave rise only to Gly, the production rate of Gly (Gly PR) was calculated from [1-13C]Gly and [1-14C]Sar infusions using either the primary pools (plasma Gly and HA, respectively) or the secondary pools (HA and plasma Gly, respectively). The results were explained by a liver-plasma Gly exchange model. The whole body Gly irreversible loss, i.e., direct loss from plasma and liver, was calculated from this model to be 832 +/- 58 mumol.kg-1.h-1, showing that the estimation of Gly PR with [1-13C]Gly infusion and plasma Gly enrichment (599 +/- 56 mumol.kg-1.h-1) was a significant underestimate of the true value.(ABSTRACT TRUNCATED AT 250 WORDS)

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Immune system stimulation increases the irreversible loss of cysteine to taurine, but not sulfate, in starter pigs

Journal of Animal Science ◽

10.1093/jas/skaa001 ◽

2020 ◽

Vol 98 (1) ◽

Cited By ~ 1

Author(s):

Anoosh Rakhshandeh ◽

Cornelis F M de Lange ◽

John K Htoo ◽

Amanda R Rakhshandeh

Keyword(s):

Immune System ◽

Plasma Concentrations ◽

Growing Pigs ◽

Whole Body ◽

Synthesis Rate ◽

Irreversible Loss ◽

Minimal Impact ◽

Fed State ◽

E Coli ◽

Isotope Tracer

Abstract An isotope tracer study was conducted to evaluate the effects of immune system stimulation (ISS) on the irreversible loss of cysteine (Cys) to taurine (Tau) and sulfate (SO4), as well as glutathione (GSH) synthesis, during the fed state in pigs. We previously have reported that ISS increases plasma Cys flux and the GSH synthesis rate at the tissue and whole-body levels in growing pigs. Thus, the current article presents the data on the irreversible loss of Cys during ISS in pigs. Ten gilts (BW: 7.0 ± 0.12 kg) were feed restricted a sulfur amino acids (SAA) limiting diet and injected twice with either saline (n = 4) or increasing amounts of E. coli lipopolysaccharide (n = 6). The day after the second injection, a 5-h primed continuous intravenous infusion of 35S-Cys was conducted. ISS reduced plasma Cys and total SAA concentrations (16% and 21%, respectively; P < 0.05). However, ISS had no effect on the plasma concentrations of Tau and SO4, nor did it affect the appearance of 35S in plasma Tau, plasma SO4, urinary Tau, or urinary SO4 (P > 0.19). On a whole-body basis and including urinary excretion, ISS increased the appearance of 35S in Tau by 67% (P < 0.05), but tended to decrease the appearance of 35S in SO4 by 22% (P < 0.09). Overall, the current findings indicate that during ISS, decreased plasma SAA concentrations and increased plasma Cys flux are attributed in part to increased rates of Cys conversion to Tau, but not Cys catabolism to SO4. Thus, increased utilization of Cys for the synthesis of immune system metabolites, such as GSH and Tau, is likely the main contributor to increased Cys flux during ISS in pigs. In addition, the irreversible loss of Cys during ISS is small and has a minimal impact on the daily SAA requirements of starter pigs.

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Association between Oxygen Consumption and Surface Electromyographic Amplitude and Its Variation within Individual Calf Muscles during Walking at Various Speeds

Sensors ◽

10.3390/s21051748 ◽

2021 ◽

Vol 21 (5) ◽

pp. 1748

Author(s):

Kohei Watanabe ◽

Shideh Narouei

Keyword(s):

Oxygen Consumption ◽

Spatial Variation ◽

Metabolic Response ◽

Correlation Coefficients ◽

Surface Emg ◽

Medial Gastrocnemius ◽

Whole Body ◽

Young Males ◽

Emg Amplitude ◽

Calf Muscles

Surface electromyography (EMG) has been used to estimate muscle work and physiological burden of the whole body during human movements. However, there are spatial variations in surface EMG responses within individual muscles. The aim of this study was to investigate the relation between oxygen consumption and surface EMG responses of lower leg muscles during walking at various speeds and to quantify its spatial variation within an individual muscle. Nine young males walked on a treadmill at four speeds: preferred minus 1 km/h, preferred, preferred plus 1 km/h, and preferred plus 2 km/h, and the metabolic response was measured based on the expired gas. High-density surface EMG of the tibialis anterior (TA), medial gastrocnemius (MG), lateral gastrocnemius, and soleus muscles was performed using 64 two-dimensional electrode grids. Correlation coefficients between oxygen consumption and the surface EMG amplitude were calculated across the gait speeds for each channel in the electrode grid and for individual muscles. Mean correlation coefficients across electrodes were 0.69–0.87 for the four individual muscles, and the spatial variation of correlation between the surface EMG amplitude and oxygen consumption within an electrode grid was significantly greater in MG muscle than in TA muscle (Quartile deviations: 0.24 for MG and 0.02 for TA, p < 0.05). These results suggest that the physiological burden of the whole body during gait at various speeds can be estimated from the surface EMG amplitude of calf muscles, but we need to note its spatial distribution within the MG muscle.

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Rare genetic variants affecting urine metabolite levels link population variation to inborn errors of metabolism

Nature Communications ◽

10.1038/s41467-020-20877-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yurong Cheng ◽

◽

Pascal Schlosser ◽

Johannes Hertel ◽

Peggy Sekula ◽

...

Keyword(s):

Genetic Variants ◽

Inborn Errors Of Metabolism ◽

Cell Types ◽

Population Variation ◽

Whole Body ◽

Sequencing Data ◽

Inborn Errors ◽

Data Links ◽

Liver And Kidney ◽

Constraint Based Modeling

AbstractMetabolite levels in urine may provide insights into genetic mechanisms shaping their related pathways. We therefore investigate the cumulative contribution of rare, exonic genetic variants on urine levels of 1487 metabolites and 53,714 metabolite ratios among 4864 GCKD study participants. Here we report the detection of 128 significant associations involving 30 unique genes, 16 of which are known to underlie inborn errors of metabolism. The 30 genes are strongly enriched for shared expression in liver and kidney (odds ratio = 65, p-FDR = 3e−7), with hepatocytes and proximal tubule cells as driving cell types. Use of UK Biobank whole-exome sequencing data links genes to diseases connected to the identified metabolites. In silico constraint-based modeling of gene knockouts in a virtual whole-body, organ-resolved metabolic human correctly predicts the observed direction of metabolite changes, highlighting the potential of linking population genetics to modeling. Our study implicates candidate variants and genes for inborn errors of metabolism.

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Physiologically Based Pharmacokinetic Models of Probenecid and Furosemide to Predict Transporter Mediated Drug-Drug Interactions

Pharmaceutical Research ◽

10.1007/s11095-020-02964-z ◽

2020 ◽

Vol 37 (12) ◽

Author(s):

Hannah Britz ◽

Nina Hanke ◽

Mitchell E. Taub ◽

Ting Wang ◽

Bhagwat Prasad ◽

...

Keyword(s):

Plasma Concentration ◽

Organic Anion ◽

Plasma Concentrations ◽

Whole Body ◽

Time Profiles ◽

Pbpk Models ◽

Physiologically Based Pharmacokinetic ◽

Concentration Time ◽

Anion Transporter ◽

Physiologically Based

Abstract Purpose To provide whole-body physiologically based pharmacokinetic (PBPK) models of the potent clinical organic anion transporter (OAT) inhibitor probenecid and the clinical OAT victim drug furosemide for their application in transporter-based drug-drug interaction (DDI) modeling. Methods PBPK models of probenecid and furosemide were developed in PK-Sim®. Drug-dependent parameters and plasma concentration-time profiles following intravenous and oral probenecid and furosemide administration were gathered from literature and used for model development. For model evaluation, plasma concentration-time profiles, areas under the plasma concentration–time curve (AUC) and peak plasma concentrations (Cmax) were predicted and compared to observed data. In addition, the models were applied to predict the outcome of clinical DDI studies. Results The developed models accurately describe the reported plasma concentrations of 27 clinical probenecid studies and of 42 studies using furosemide. Furthermore, application of these models to predict the probenecid-furosemide and probenecid-rifampicin DDIs demonstrates their good performance, with 6/7 of the predicted DDI AUC ratios and 4/5 of the predicted DDI Cmax ratios within 1.25-fold of the observed values, and all predicted DDI AUC and Cmax ratios within 2.0-fold. Conclusions Whole-body PBPK models of probenecid and furosemide were built and evaluated, providing useful tools to support the investigation of transporter mediated DDIs.

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Effects of guanidinoacetic acid supplementation on nitrogen retention and methionine flux in cattle

Journal of Animal Science ◽

10.1093/jas/skab172 ◽

2021 ◽

Vol 99 (6) ◽

Author(s):

Mehrnaz Ardalan ◽

Matt D Miesner ◽

Christopher D Reinhardt ◽

Daniel U Thomson ◽

Cheryl K Armendariz ◽

...

Keyword(s):

Plasma Concentrations ◽

Nitrogen Retention ◽

High Energy ◽

Plasma Homocysteine ◽

Whole Body ◽

Lean Tissue ◽

Methyl Group ◽

Guanidinoacetic Acid ◽

Protein Supply ◽

Plot Design

Abstract Creatine stores high-energy phosphate bonds in muscle and is synthesized in the liver through methylation of guanidinoacetic acid (GAA). Supplementation of GAA may therefore increase methyl group requirements, and this may affect methyl group utilization. Our experiment evaluated the metabolic responses of growing cattle to postruminal supplementation of GAA, in a model where methionine (Met) was deficient, with and without Met supplementation. Seven ruminally cannulated Holstein steers (161 kg initial body weight [BW]) were limit-fed a soybean hull-based diet (2.7 kg/d dry matter) and received continuous abomasal infusions of an essential amino acid (AA) mixture devoid of Met to ensure that no AA besides Met limited animal performance. To provide energy without increasing the microbial protein supply, all steers received ruminal infusions of 200 g/d acetic acid, 200 g/d propionic acid, and 50 g/d butyric acid, as well as abomasal infusions of 300 g/d glucose. Treatments, provided abomasally, were arranged as a 2 × 3 factorial in a split-plot design, and included 0 or 6 g/d of l-Met and 0, 7.5, and 15 g/d of GAA. The experiment included six 10-d periods. Whole body Met flux was measured using continuous jugular infusion of 1-13C-l-Met and methyl-2H3-l-Met. Nitrogen retention was elevated by Met supplementation (P < 0.01). Supplementation with GAA tended to increase N retention when it was supplemented along with Met, but not when it was supplemented without Met. Supplementing GAA linearly increased plasma concentrations of GAA and creatine (P < 0.001), but treatments did not affect urinary excretion of GAA, creatine, or creatinine. Supplementation with Met decreased plasma homocysteine (P < 0.01). Supplementation of GAA tended (P = 0.10) to increase plasma homocysteine when no Met was supplemented, but not when 6 g/d Met was provided. Protein synthesis and protein degradation were both increased by GAA supplementation when no Met was supplemented, but decreased by GAA supplementation when 6 g/d Met were provided. Loss of Met through transsulfuration was increased by Met supplementation, whereas synthesis of Met from remethylation of homocysteine was decreased by Met supplementation. No differences in transmethylation, transsulfuration, or remethylation reactions were observed in response to GAA supplementation. The administration of GAA, when methyl groups are not limiting, has the potential to improve lean tissue deposition and cattle growth.

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Buprenorphine Metabolites, Buprenorphine-3-glucuronide and Norbuprenorphine-3-glucuronide, Are Biologically Active

Anesthesiology ◽

10.1097/aln.0b013e318238fea0 ◽

2011 ◽

Vol 115 (6) ◽

pp. 1251-1260 ◽

Cited By ~ 32

Author(s):

Sarah M. Brown ◽

Michael Holtzman ◽

Thomas Kim ◽

Evan D. Kharasch

Keyword(s):

Radioligand Binding ◽

Competitive Inhibition ◽

Antinociceptive Effect ◽

Plasma Concentrations ◽

Parent Drug ◽

Biologically Active ◽

Whole Body ◽

Tail Flick ◽

High Affinity

Background The long-lasting high-affinity opioid buprenorphine has complex pharmacology, including ceiling effects with respect to analgesia and respiratory depression. Plasma concentrations of the major buprenorphine metabolites norbuprenorphine, buprenorphine-3-glucuronide, and norbuprenorphine-3-glucuronide approximate or exceed those of the parent drug. Buprenorphine glucuronide metabolites pharmacology is undefined. This investigation determined binding and pharmacologic activity of the two glucuronide metabolites, and in comparison with buprenorphine and norbuprenorphine. Methods Competitive inhibition of radioligand binding to human μ, κ, and δ opioid and nociceptin receptors was used to determine glucuronide binding affinities for these receptors. Common opiate effects were assessed in vivo in SwissWebster mice. Antinociception was assessed using a tail-flick assay, respiratory effects were measured using unrestrained whole-body plethysmography, and sedation was assessed by inhibition of locomotion measured by open-field testing. Results Buprenorphine-3-glucuronide had high affinity for human μ (Ki [inhibition constant] = 4.9 ± 2.7 pM), δ (Ki = 270 ± 0.4 nM), and nociceptin (Ki = 36 ± 0.3 μM) but not κ receptors. Norbuprenorphine-3-glucuronide had affinity for human κ (Ki = 300 ± 0.5 nM) and nociceptin (Ki = 18 ± 0.2 μM) but not μ or δ receptors. At the dose tested, buprenorphine-3-glucuronide had a small antinociceptive effect. Neither glucuronide had significant effects on respiratory rate, but norbuprenorphine-3-glucuronide decreased tidal volume. Norbuprenorphine-3-glucuronide also caused sedation. Conclusions Both glucuronide metabolites of buprenorphine are biologically active at doses relevant to metabolite exposures, which occur after buprenorphine. Activity of the glucuronides may contribute to the overall pharmacology of buprenorphine.

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