Myocardial substrate utilization in dogs following endotoxin administration

Spitzer, John J.; Bechtel, A. A.; Archer, L. T.; Black, Mary Jo; Hinshaw, Lerner B.

doi:10.1152/ajplegacy.1974.227.1.132

Cited by 37 publications

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“…The heart oxidizes fatty acids to generate ATP to provide energy. Studies have shown that, during sepsis, the ability of the heart to oxidize fatty acids is impaired and it is likely that this decrease in energy production contributes to the cardiac failure that often accompanies sepsis (33,34,36,55). The present study illustrates a mechanism by which sepsis could impair fatty acid oxidation and, consequently, cardiac function.…”

Section: Discussionmentioning

confidence: 53%

“…Two isoforms of this enzyme are expressed in the heart, with CPT I␤ accounting for most of the activity (64). Within the mitochondria, the fatty acids undergo ␤-oxidation, which generates the ATP required for cardiac function.In association with the decrease in cardiac output during sepsis and after LPS administration, most, but not all, investigators have observed a reduction in the uptake and oxidation of fatty acids and the accumulation of triglycerides in the myocytes (29,33,34,36,55,63). Our laboratory and others (2,21,(37)(38)(39) have shown that the expression of many of the proteins that play key roles in fatty acid oxidation, such as LPL, FATP, FAT/CD36, FACS, and H-FABP, is decreased in the heart after LPS and/or cytokine administration and that these decreases could account for the reduction in cardiac fatty acid oxidation.…”

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confidence: 99%

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Altered expression of nuclear hormone receptors and coactivators in mouse heart during the acute-phase response

Feingold

Kim

Shigenaga

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

127

108

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. Altered expression of nuclear hormone receptors and coactivators in mouse heart during the acute-phase response. Am J Physiol Endocrinol Metab 286: E201-E207, 2004; 10.1152/ ajpendo.00205.2003.-Severe sepsis results in the decreased uptake and oxidation of fatty acids in the heart and cardiac failure. Some of the key proteins required for fatty acid uptake and oxidation in the heart have been shown to be downregulated after endotoxin (LPS) administration. The nuclear hormone receptors, peroxisome proliferator-activated receptor (PPAR) and thyroid receptor (TR), which heterodimerize with the retinoid X receptor (RXR), are important regulators of fatty acid metabolism and decrease in the liver after LPS administration. In the present study, we demonstrate that LPS treatment produces a rapid and marked decrease in the mRNA levels of all three RXR isoforms, PPAR␣ and PPAR␦, and TR␣ and TR␤ in the heart. Moreover, LPS administration also decreased the expression of the coactivators CREB-binding protein (CBP)/p300, steroid receptor coactivator (SRC)-1, SRC-3, TR-associated protein (TRAP)220, and PPAR␥ coactivator (PGC)-1, all of which are required for the transcriptional activity of RXR-PPAR and RXR-TR. In addition, the mRNA levels of the target genes malic enzyme, Spot 14, sarcoplasmic reticulum Ca 2ϩ -ATPase, or SERCA2, the VLDL receptor, fatty acylCoA synthetase, fatty acid transporter/CD36, carnitine palmitoyltransferase I␤, and lipoprotein lipase decrease in the heart after LPS treatment. The decrease in expression of RXR␣, -␤, and -␥, PPAR␣ and -␦, and TR␣ and -␤, and of the coactivators CBP/p300, SRC-1, SRC-3, TRAP220, and PGC-1 and the genes they regulate, induced by LPS in the heart, could account for the decreased expression of key proteins required for fatty acid oxidation and thereby play an important role in cardiac contractility. These alterations could contribute to the myocardial dysfunction that occurs during sepsis. endotoxin; fatty acid oxidation; cardiac contractility SEVERE SEPSIS RESULTS IN CARDIAC FAILURE, and this effect can be mimicked by endotoxin (LPS) administration (11,48,50,56). Initially, during sepsis and after LPS administration, there is a decrease in systemic resistance and either normal or increased cardiac output (11,48,50,56). However, with time, cardiac output decreases due to a decrease in both contractility and heart rate (11,48,50,56). Similar effects on cardiac function are observed with the administration of TNF and IL-1 (7,42,44,47), cytokines that mediate the effects of LPS (7,15).For the heart to function as a pump, constant generation of ATP is required, which is formed by the oxidation of fatty acids, glucose, or lactate (59). Fatty acid oxidation produces the most energy per molecule, and because of the high-energy demands of the heart, fatty acids are the primary fuel for cardiac ATP generation (58, 59). The oxidation of fatty acids by cardiac myocytes involves a large number of enzymes and transporters. One of the initial steps is the hydrolysis of triglycerides c...

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Section: Discussionmentioning

confidence: 53%

mentioning

confidence: 99%

Altered expression of nuclear hormone receptors and coactivators in mouse heart during the acute-phase response

Feingold

Kim

Shigenaga

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

127

108

View full text Add to dashboard Cite

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“…In our experiment LDH activity in the myocardial muscle markedly increased in an early stage (3-6 hr) of endotoxin poisoning, and the activity gradually declined and became somewhat lower than that in control mice at 48 hr. Spitzer et al (33) found that myocardial utilization of blood lactate in dogs was markedly elevated at 2-4 hr in endotoxin shock, and that the contribution of FFA to the utilization of myocardial energy was greatly diminished. A shift in myocardial metabolism as observed in endotoxin-poisoned dogs was also found in mice in our study.…”

Section: Discussionmentioning

confidence: 99%

“…More recently, investigators have confined their interests to the metabolic alterations which develop during Gram-negative sepsis or endotoxin shock (7, 8, 13, 14, 17, 19, 23, 26, 27,33).…”

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Changes in the Activities of Enzymes, Especially Lactate Dehydrogenase, in Endotoxin‐Poisoned Mice

Sakaguchi

Tsunoda

1979

Microbiology and Immunology

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Carbohydrate metabolic disorders were investigated by means of enzyme activities in mice (ddYS) injected intraperitoneally with endotoxin from Salmonella typhimurium. The mice exhibited hyperglycemia 2 hr after administration of endotoxin and hypoglycemia at 18 hr. Activity of hepatic phosphorylase in the endotoxin-poisoned mice at 2 hr was slightly higher than that in the control mice, whereas the level of this activity was not significantly different from that in the controls after 18 hr. Glucose-6-phosphatase activity in the poisoned mice increased by 2 hr after injection, but decreased by 18 hr.The blood lactate level in the poisoned mice transiently decreased until 3 hr after injection, but the mice exhibited a marked lactacidemia by 8-24 hr. The time course of lactate dehydrogenase (LDH) activity in various tissues was examined in mice injected with endotoxin. The activity of hepatic LDH declined to about two-thirds of that of the control mice after 16 hr, and was restored to the normal level by 48 hr. LDH in the cardiac muscle was markedly activated (by about 37 %) in the early period (3-6 hr) after administration of endotoxin, and this activity gradually declined. However, the activity of LDH in the skeletal muscle showed a tendency similar to the rise and fall of the levels of blood lactate, and was restored to the normal value at 72 hr after injection. On the other hand, the serum LDH activity in the poisoned mice increased about 1.75-fold by 16 hr after injection. Mice injected with endotoxin exhibited a leakage of the isozymes LDH 3 and 5, but the origin of the leakage is uncertain. Similar elevation in the activities of transaminases (GPT and GOT) and malate dehydrogenase was found in the mouse serum at 16 hr after injection of endotoxin.There have been many studies on disorders in carbohydrate metabolism in experimental animals injected with endotoxin (3-6, 20, 21, 24, 25, 28, 31, 38, 39). More recently, investigators have confined their interests to the metabolic alterations which develop during Gram-negative sepsis or endotoxin shock (7, 8, 13, 14, 17, 19, 23, 26, 27,33).It is well known that endotoxin-poisoned animals initially exhibit hyperglycemia, which is followed by a prompt fall in blood sugar to a hypoglycemic level with a concomitant decrease in the levels of liver and muscular glycogen, producing a profound lactacidemia. Endotoxemia depresses both in vivo gluconeogenesis and gly-605

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“…Previous studies have shown that there is a marked decrease in myocardial NEFA uptake during septic shock. 12 Furthermore, a shift to lactate has been reported in endotoxin shock. 2 As myocardial dysfunctions can occur early during septic shock, it was considered of interest to investigate NEFA and lactate uptake by the myocardium in patients with severe sepsis.…”

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confidence: 99%

Individual Free Fatty Acids and Lactate Uptake in the Human Heart during Severe Sepsis

et al. 1988

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SUMMARY. Coronary haemodynamics and myocardial metabolism of nonesterified fatty acids (NEFA) and lactate were studied in 11 patients with severe sepsis, and compared to 10 control subjects. Coronary sinus blood flow was evaluated by thermodilution. Arterial and coronary sinus blood samples were collected for tbe measurement of lactate and total and individual NEFA concentrations both in septic and control patients. There was an increase in lactate and total NEFA arterial concentrations with a marked increase in palmitic and linolenic acids. The uptake of the main NEFA (C14:0 to C18:2) was significantly decreased. In the control group, individual NEFA uptake was proportional to their arterial concentrations. This relationship was not observed in patients with sepsis: there was no preferential extraction of any particular NEFA. Furthermore, in patients with sepsis, myocardial oxygen consumption did not correlate with NEFA, but only with lactate uptake. Alterations in NEFA uptake were found to be constant during severe sepsis and are consistent with major disturbances in myocardial metabolism.Sepsis continues to be one of the principal causes of death in intensive care units. Myocardial failure is often a result of septic shock, but the mechanism of this dysfunction remains obscure. 1. 2 Previous results have shown the presence of a circulating myocardial depressant substance inducing myocardial failure in vitro, but its role in vivo remains controversial.v 4 Nevertheless, increasing attention has been directed to the changes in myocardial substrate utilisation occurring during sepsis which might induce cardiac depression.S In the human heart, non-esterified fatty acids (NEFA) are the main source of energy under aerobic conditions. 6 , 7 Sixty per cent, and more, of the energy used by myocardial cells is supplied by NEFA oxidation and nearly 30% is derived from lactate.f The individual fatty acids are extracted in different amounts by the myocardium: there is a strong correlation between NEFA uptake and arterial NEFA concentrations both in heart and skeletal mascle.?: 10 In sepsis, NEFA levels have Correspondence: Pr.

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Myocardial substrate utilization in dogs following endotoxin administration

Cited by 37 publications

References 1 publication

Altered expression of nuclear hormone receptors and coactivators in mouse heart during the acute-phase response

Altered expression of nuclear hormone receptors and coactivators in mouse heart during the acute-phase response

Changes in the Activities of Enzymes, Especially Lactate Dehydrogenase, in Endotoxin‐Poisoned Mice

Individual Free Fatty Acids and Lactate Uptake in the Human Heart during Severe Sepsis

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