Limited transfer of cytosolic NADH into mitochondria at high cardiac workload

2004 ◽  
Vol 286 (6) ◽  
pp. H2237-H2242 ◽  
Author(s):  
J. Michael O'Donnell ◽  
Raymond K. Kudej ◽  
Kathyrn F. LaNoue ◽  
Stephen F. Vatner ◽  
E. Douglas Lewandowski
Keyword(s):  
Blood Flow ◽  
Glucose Oxidation ◽  
Lactate Production ◽  
Atp Synthesis ◽  
Rate Pressure Product ◽  
Myocardial Tissue ◽  
High Workload ◽  
Energy Synthesis ◽  
High Work ◽  
Reducing Equivalents

Glycolysis supplements energy synthesis at high cardiac workloads, producing not only ATP but also cytosolic NADH and pyruvate for oxidative ATP synthesis. Despite adequate Po2, speculation exists that not all cytosolic NADH is oxidized by the mitochondria, leading to lactate production. In this study, we elucidate the mechanism for limited cytosolic NADH oxidation and increased lactate production at high workload despite adequate myocardial blood flow and oxygenation. Reducing equivalents from glycolysis enter mitochondria via exchange of mitochondrial α-ketoglutarate (α-KG) for cytosolic malate. This exchange was monitored at baseline and at high workloads by comparing 13C enrichment between the products of α-KG oxidation (succinate) and α-KG efflux from mitochondria (glutamate). Under general anesthesia, a left thoracotomy was performed on 14 dogs and [2-13C]acetate was infused into the left anterior descending artery for 40 min. The rate-pressure product was 9,035 ± 1,972 and 21,659 ± 5,266 mmHg·beats·min−1 ( n = 7) at baseline ( n = 7) and with dobutamine, respectively. 13C enrichment of succinate was 57 ± 10% at baseline and 45 ± 13% at elevated workload (not significant), confirming oxidation of [2-13C]acetate. However, cytosolic glutamate enrichment, a marker of cytosolic NADH transfer to mitochondria, was dramatically reduced at high cardiac workload (11 ± 1%) vs. baseline (50 ± 14%, P < 0.05). This reduced exchange of 13C from α-KG to cytosolic glutamate at high work indicates reduced shuttling of cytosolic reducing equivalents into the mitochondria. Myocardial tissue lactate increased 78%, countering this reduced oxidation of cytosolic NADH. The findings elucidate a contributing mechanism to glycolysis outpacing glucose oxidation in the absence of myocardial ischemia.

Abstract 12622: Western Diet for One Month Impairs Myocardial Energetics and Both Systolic and Diastolic Pump Function in the Mouse Heart

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Ivan Luptak ◽  
Aaron L Sverdlov ◽  
Aly Elezaby ◽  
Edward J Miller ◽  
David R Pimentel ◽  
...  
Keyword(s):  
Diastolic Dysfunction ◽  
Mitochondrial Dysfunction ◽  
Systolic Function ◽  
Atp Synthesis ◽  
Contractile Reserve ◽  
31P Nmr Spectroscopy ◽  
Pump Function ◽  
High Workload ◽  
Myocardial Energetics ◽  
Intact Heart

Background and Significance: Metabolic heart disease(MHD) is common in patients with obesity, type 2 diabetes and/or metabolic syndrome. We found cardiac mitochondrial dysfunction in mice with obesity-related MHD due to consumption of a high fat high sucrose (HFHS) diet. The effects of diet-induced obesity on cardiac energetics and pump function in the intact organ are largely unknown. Hypothesis: We tested the hypothesis that cardiac mitochondrial dysfunction due to HFHS diet for one month impairs energetic and contractile reserve in the intact heart. Methods and Results: Mice were fed a HFHS or control diet (CD) for 1 month. In isolated cardiac mitochondria from HFHS-fed mice (vs. CD) the maximal rate of ATP synthesis was decreased for complex I (down by 42%; p<0.05) and II (down by 37%; p<0.05) substrates. We measured myocardial energetics in isolated perfused hearts using 31P NMR spectroscopy at baseline (450 bpm, 2 mM Ca++) and high workload (600 bpm, 4 mM Ca++) in HFHS (n=7) and CD (n=8) hearts. In HFHS-fed hearts, myocardial ATP concentration was the same at baseline (10.5±0.4 vs 10.4±0.5 mM) and high workload (7.4±0.9 vs. 7.5±0.5 mM) as that of CD hearts. However, in HFHS-fed hearts the concentration of phosphocreatine, which reflects energy reserve, was decreased at baseline (13±0.7 vs. 17.5±0.8 mM; p<0.01) and decreased further at high workload (down to 7.3±0.7; p<0.01 vs. baseline and p<0.01 vs. CD at 10.5±0.4 mM) - indicating a mismatch between ATP production and utilization. In HFHS hearts, the diastolic pressure-volume relationship was shifted upward and leftward at baseline, indicative of diastolic dysfunction. In HFHS hearts, baseline systolic function was preserved (rate pressure product 41,600±2,200 vs. 41,000±2,000 mmHg/min), but was decreased at high workload (54,800±7,200 vs. 85,300±4,300 mmHg/min; p<0.01 vs. CD), reflecting an impaired contractile reserve. Conclusion: Consumption of a HFHS diet for one month causes cardiac mitochondrial dysfunction with reduced ATP synthesis leading to impaired energetic reserve in the intact heart. Diastolic dysfunction at rest and the impaired ability to increase systolic function with increased work demands may result from impaired energetics in MHD.

scholarly journals Limited capacity for glucose oxidation in fetal sheep with intrauterine growth restriction

2015 ◽  
Vol 309 (8) ◽  
pp. R920-R928 ◽  
Author(s):  
Laura D. Brown ◽  
Paul J. Rozance ◽  
Jennifer L. Bruce ◽  
Jacob E. Friedman ◽  
William W. Hay ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mrna Expression ◽  
Glucose Oxidation ◽  
Fetal Liver ◽  
Lactate Production ◽  
Glucose Production ◽  
Limited Capacity ◽  
Fetal Sheep ◽  
Intrauterine Growth ◽  
Insulin Clamp

Intrauterine growth-restricted (IUGR) fetal sheep, produced by placental insufficiency, have lower oxygen concentrations, higher lactate concentrations, and increased hepatic glucose production that is resistant to suppression by insulin. We hypothesized that increased lactate production in the IUGR fetus results from reduced glucose oxidation, during basal and maximal insulin-stimulated conditions, and is used to support glucose production. To test this, studies were performed in late-gestation control (CON) and IUGR fetal sheep under basal and hyperinsulinemic-clamp conditions. The basal glucose oxidation rate was similar and increased by 30–40% during insulin clamp in CON and IUGR fetuses ( P < 0.005). However, the fraction of glucose oxidized was 15% lower in IUGR fetuses during basal and insulin-clamp periods ( P = 0.05). IUGR fetuses also had four-fold higher lactate concentrations ( P < 0.001) and lower lactate uptake rates ( P < 0.05). In IUGR fetal muscle and liver, mRNA expression of pyruvate dehydrogenase kinase ( PDK4), an inhibitor of glucose oxidation, was increased over fourfold. In IUGR fetal liver, but not skeletal muscle, mRNA expression of lactate dehydrogenase A ( LDHA) was increased nearly fivefold. Hepatic expression of the gluconeogenic genes, phosphoenolpyruvate carboxykinase ( PCK)1, and PCK2, was correlated with expression of PDK4 and LDHA. Collectively, these in vivo and tissue data support limited capacity for glucose oxidation in the IUGR fetus via increased PDK4 in skeletal muscle and liver. We speculate that lactate production also is increased, which may supply carbon for glucose production in the IUGR fetal liver.

Abstract 2831: Endomyocardial-to-Epimyocardial Blood Flow Ratio Distinguishes Severity of Coronary Artery Disease: A Perfusion CMR Study

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Amit R Patel ◽  
Patrick F Antkowiak ◽  
Kiran R Nandalur ◽  
Vishal Arora ◽  
Christopher M Kramer ◽  
...  
Keyword(s):  
Blood Flow ◽  
Arterial Input Function ◽  
Tissue Perfusion ◽  
Input Function ◽  
Rate Pressure Product ◽  
Planar Imaging ◽  
Clinical Patient ◽  
Blood Flow Ratio ◽  
Artery Disease ◽  
Perfusion Cmr

Background: Ischemia propagates as a wave front from the endocardial (ENDO) to the epicardial (EPI) surface. Normally, myocardial blood flow (MBF) is higher in the ENDO than EPI. We hypothesized that the ENDO/EPI ratio could differentiate the severity of coronary stenoses in a clinical patient population. Methods: Perfusion CMR was performed in 29 patients within 30 days of x-ray angiography and quantitative coronary analysis. During adenosine infusion and at rest, dual boluses of Gd-DTPA were infused (4ml/s) to quantify arterial input function (0.0075mM/kg) and tissue perfusion (0.075mM/kg) in 3 short axis slices using hybrid gradient echo/echo planar imaging. ENDO and EPI MBF for rest and stress were estimated by determining the peak amplitude of the impulse response derived from Fermi function deconvolution. Stress and rest ENDO/EPI ratios were calculated and then corrected (corr) for rate-pressure product (RPP) using the formula ENDO/EPI * (SBP*HR*10 −4 ). Results: Coronary stenosis (CS) >50% was present in 23 of 29 patients. Hypertension, diabetes, and dyslipidemia were present in 23, 9, and 26 patients, respectively. Stress corrENDO/EPI (mean±SE) was inversely related to CS (CS<50% = 1.356 ± 0.030, CS 50–70% = 1.266 ± 0.029, and CS>70% = 1.149 ± 0.039; p<0.05) (Figure ). The relationship persisted after exclusion of the 56 segments with a myocardial scar (p<0.05). No relationship existed between CS and rest ENDO/EPI, rest corrENDO/EPI, or uncorrected stress ENDO/EPI. Conclusions: Stress corrENDO/EPI is inversely related to the severity of CS. Quantitative stress endo/epi ratios can distinguish intermediate from severe stenoses in patients with known or suspected CS.

Influence of mild exercise at the lactate threshold on glucose effectiveness

1999 ◽  
Vol 87 (6) ◽  
pp. 2305-2310 ◽  
Author(s):  
Makoto Sakamoto ◽  
Yasuki Higaki ◽  
Yuichiro Nishida ◽  
Akira Kiyonaga ◽  
Munehiro Shindo ◽  
...  
Keyword(s):  
Blood Flow ◽  
Lactate Threshold ◽  
Lactate Production ◽  
Area Under The Curve ◽  
Young Male ◽  
Threshold Level ◽  
Tolerance Test ◽  
Intravenous Glucose Tolerance Test ◽  
Intravenous Glucose ◽  
Glucose Effectiveness

The effect of a single bout of mild exercise on glucose effectiveness (SG) and insulin sensitivity (SI) was studied in six young male subjects by using a minimal model. An intravenous glucose tolerance test was performed under two conditions as follows: 1) 25 min after a bout of exercise on a cycle ergometer at the lactate threshold level for 60 min (Ex) and 2) without any prior exercise (Con). Leg blood flow (LBF) was also measured by strain-gauge plethysmography simultaneously with blood sampling. SI did not significantly change after exercise (18.1 ± 1.5 vs. 17.7 ± 1.9 × 10−5 min/pM), whereas SG significantly increased (0.016 ± 0.002 vs. 0.025 ± 0.002 min−1, P < 0.01). The increased blood flow after exercise remained high during the time period for measurement of the glucose disappearance constant and may be a determinant of SG. The incremental lactate area under the curve until insulin loading was also significantly higher in Ex than in Con (2.6 ± 0.9 vs. −3.5 ± 1.5 mM/min, P < 0.05). These results suggest that increased SG after mild exercise may be due, at least in part, to increased LBF and lactate production under a hyperglycemic state.

Effect of dichloroacetate on mechanical performance and metabolism of compromised diaphragm muscle

1992 ◽  
Vol 72 (3) ◽  
pp. 1149-1155 ◽  
Author(s):  
B. P. deBoisblanc ◽  
K. Meszaros ◽  
A. Burns ◽  
G. J. Bagby ◽  
S. Nelson ◽  
...  
Keyword(s):  
Glucose Oxidation ◽  
Mechanical Performance ◽  
Lactate Production ◽  
Diaphragm Muscle ◽  
Tetanic Stimulation ◽  
Lactate Oxidation ◽  
Diaphragmatic Fatigue ◽  
Tension Generation

We investigated the effect of dichloroacetate (DCA) on tension generation and carbohydrate metabolism of the rat diaphragm in vitro. Isolated diaphragms were placed in individual organ chambers and were hooked to force-displacement transducers. Net lactate production and glucose and lactate oxidation were measured in vitro. Diaphragmatic fatigue was precipitated by in vivo endotoxemic shock, by in vitro hypoxia, or by in vitro repetitive tetanic stimulation. In diaphragms isolated from endotoxemic rats, DCA increased tension generation by 30 and 20% at stimulation frequencies of 20 and 100 Hz, respectively. Associated with changes in mechanical performance, DCA reduced net lactate production by 53% after 60 min of incubation and increased glucose oxidation 54% but had no effect on lactate oxidation. During in vitro hypoxia, DCA reduced net diaphragmatic lactate production by 30% and increased glucose oxidation by 45% but did not attenuate hypoxic fatigue. DCA had no effect on tension generation during repetitive tetanic stimulation. We conclude that DCA improves in vitro diaphragmatic fatigue due to endotoxicosis but not due to hypoxia or repetitive stimulation.

Effects of varying hematocrit on intestinal oxygen uptake in neonatal lambs

1985 ◽  
Vol 248 (4) ◽  
pp. G432-G436 ◽  
Author(s):  
I. R. Holzman ◽  
B. Tabata ◽  
D. I. Edelstone
Keyword(s):  
Blood Flow ◽  
Anaerobic Metabolism ◽  
Lactate Production ◽  
Oxygen Availability ◽  
Intestinal Blood Flow ◽  
Oxygen Extraction ◽  
Base Line ◽  
Wide Range ◽  
O2 Extraction ◽  
Neonatal Lambs

We chronically catheterized 15 newborn lambs (9.5 +/- 2.8 days) and measured intestinal blood flow (Qi) by the radionuclide microsphere technique at hematocrit levels ranging from 10 to 55%. Seven animals were made progressively anemic and eight polycythemic by means of exchange transfusions. Using the Fick principle, we calculated intestinal oxygen delivery (Di o2), oxygen consumption (Vi o2), and oxygen extraction. Initial base-line values were Qi = 195.5 ml . min-1 . 100 g intestine-1, Di o2 = 22.1 ml . min-1 . 100 g-1, Vi o2 = 4.8 ml . min-1 . 100 g-1, and O2 extraction = 22.5%. As the hematocrit was lowered, Di o2 decreased and O2 extraction increased and vice versa when the hematocrit was raised. Vi o2 remained constant, but Qi did not correlate with changes in hematocrit. However, intestinal blood flow, as a percent distribution of total blood flow, decreased with lower hematocrit levels. At no time was there any evidence of anaerobic metabolism as measured by excess lactate production. Our data indicate that the intestines of neonatal lambs are capable of maintaining their metabolic needs over a wide range of oxygen availability induced by a changing hematocrit. The primary mechanism is through alteration of oxygen extraction. Within the range of our experiments, no critically low oxygen availability was attained at which anaerobic metabolism became significant.

Cardiac performance and creatine kinase flux during inhibition of ATP synthesis in the perfused rat heart

1999 ◽  
Vol 277 (1) ◽  
pp. H308-H317 ◽  
Author(s):  
P. Mateo ◽  
V. Stepanov ◽  
B. Gillet ◽  
J.-C. Beloeil ◽  
J. A. Hoerter
Keyword(s):  
Creatine Kinase ◽  
Rat Heart ◽  
Mechanical Performance ◽  
Diastolic Pressure ◽  
Atp Synthesis ◽  
Cardiac Performance ◽  
Rate Pressure Product ◽  
Saturation Transfer ◽  
Perfused Rat Heart ◽  
Performance Rate

To study the relation among mitochondrial energy supply, cardiac performance, and energy transfer through creatine kinase (CK), two acute models of inhibition of ATP synthesis were compared in the isovolumic acetate-perfused rat heart. Similar impairments of mechanical performance (rate-pressure product, RPP) were achieved by various stepwise decreases in O2 supply ([Formula: see text] down to 20% of control) or by infusing CN (0.15–0.25 mM). The forward CK flux measured by saturation-transfer 31P NMR spectroscopy was 6.1 ± 0.4 mM/s in control hearts. Only after severe hypoxia ([Formula: see text] < 40% of control) did CK flux drop (to 1.9 ± 0.2 mM/s at[Formula: see text] = 25% of control) together with impaired systolic activity and a rise in end-diastolic pressure. In contrast, in mild hypoxia CK flux remained constant and similar to control (5.3 ± 0.5 mM/s, not significant) despite a twofold reduction in systolic activity. Similarly in all CN groups, constant CK flux was maintained for a threefold reduction in RPP, showing the absence of a relation between cardiac performance and global NMR-measured CK flux during mild ATP synthesis inhibition.

Coronary nitric oxide production controls cardiac substrate metabolism during pregnancy in the dog

2008 ◽  
Vol 294 (6) ◽  
pp. H2516-H2523 ◽  
Author(s):  
Jeffrey G. Williams ◽  
Caroline Ojaimi ◽  
Khaled Qanud ◽  
Suhua Zhang ◽  
Xiaobin Xu ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Glucose Oxidation ◽  
Atp Synthesis ◽  
Glycogen Metabolism ◽  
Cardiac Metabolism ◽  
Atp Production ◽  
Oxidative Pathway ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

The aim of this study was to examine the role of nitric oxide (NO) in the control of cardiac metabolism at 60 days of pregnancy (P60) in the dog. There was a basal increase in diastolic coronary blood flow during pregnancy and a statistically significant increase in cardiac output (55 ± 4%) and in cardiac NOx production (44 ± 4 to 59 ± 3 nmol/min, P < 0.05). Immunohistochemistry of the left ventricle showed an increase in endothelial nitric oxide synthase staining in the endothelial cells at P60. NO-dependent coronary vasodilation (Bezold-Jarisch reflex) was increased by 20% and blocked by NG-nitro-l-arginine methyl ester (l-NAME). Isotopically labeled substrates were infused to measure oleate, glucose uptake, and oxidation. Glucose oxidation was not significantly different in P60 hearts (5.4 ± 0.5 vs. 6.2 ± 0.4 μmol/min) but greatly increased in response to l-NAME injection (to 19.9 ± 0.9 μmol/min, P < 0.05). Free fatty acid (FFA) oxidation was increased in P60 (from 5.3 ± 0.6 to 10.4 ± 0.5 μmol/min, P < 0.05) and decreased in response to l-NAME (to 4.5 ± 0.5 μmol/min, P < 0.05). There was an increased oxidation of FFA for ATP production but no change in the respiratory quotient during pregnancy. Genes associated with glucose and glycogen metabolism were downregulated, whereas genes involved in FFA oxidation were elevated. The acute inhibition of NO shifts the heart away from FFA and toward glucose metabolism despite the downregulation of the carbohydrate oxidative pathway. The increase in endothelium-derived NO during pregnancy results in a tonic inhibition of glucose oxidation and reliance on FFA uptake and oxidation to support ATP synthesis in conjunction with upregulation of FFA metabolic enzymes.

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