Differential effects of heptanoate and hexanoate on myocardial citric acid cycle intermediates following ischemia-reperfusion

2006 ◽  
Vol 100 (1) ◽  
pp. 76-82 ◽  
Author(s):  
Isidore C. Okere ◽  
Tracy A. McElfresh ◽  
Daniel Z. Brunengraber ◽  
Wenjun Martini ◽  
Joseph P. Sterk ◽  
...  
Keyword(s):  
Citric Acid ◽  
Citric Acid Cycle ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Negative Control ◽  
Saline Control ◽  
Acid Cycle ◽  
Treatment Groups ◽  
Reversible Ischemia

In the normal heart, there is loss of citric acid cycle (CAC) intermediates that is matched by the entry of intermediates from outside the cycle, a process termed anaplerosis. Previous in vitro studies suggest that supplementation with anaplerotic substrates improves cardiac function during myocardial ischemia and/or reperfusion. The present investigation assessed whether treatment with the anaplerotic medium-chain fatty acid heptanoate improves contractile function during ischemia and reperfusion. The left anterior descending coronary artery of anesthetized pigs was subjected to 60 min of 60% flow reduction and 30 min of reperfusion. Three treatment groups were studied: saline control, heptanoate (0.4 mM), or hexanoate as a negative control (0.4 mM). Treatment was initiated after 30 min of ischemia and continued through reperfusion. Myocardial CAC intermediate content was not affected by ischemia-reperfusion; however, treatment with heptanoate resulted in a more than twofold increase in fumarate and malate, with no change in citrate and succinate, while treatment with hexanoate did not increase fumarate or malate but increased succinate by 1.8-fold. There were no differences among groups in lactate exchange, glucose oxidation, oxygen consumption, and contractile power. In conclusion, despite a significant increase in the content of carbon-4 CAC intermediates, treatment with heptanoate did not result in improved mechanical function of the heart in this model of reversible ischemia-reperfusion. This suggests that reduced anaplerosis and CAC dysfunction do not play a major role in contractile and metabolic derangements observed with a 60% decrease in coronary flow followed by reperfusion.

Propionyl-L-carnitine-mediated improvement in contractile function of rat hearts oxidizing acetoacetate

1995 ◽  
Vol 268 (1) ◽  
pp. H441-H447 ◽  
Author(s):  
R. R. Russell ◽  
J. I. Mommessin ◽  
H. Taegtmeyer
Keyword(s):  
Citric Acid ◽  
Citric Acid Cycle ◽  
Mechanical Performance ◽  
Ketone Bodies ◽  
Contractile Function ◽  
Sustained Improvement ◽  
Acid Cycle ◽  
Rat Hearts ◽  
Beta Hydroxybutyrate ◽  
Contractile Failure

Prior evidence has suggested that propionyl-L-carnitine improves function in ischemic hearts by providing carnitine for dissipation of acyl-CoA derivatives and propionate for enrichment of the citric acid cycle. Because contractile failure in hearts oxidizing ketone bodies is due to sequestration of free coenzyme A, which can be reversed by the addition of anaplerotic substrates that enrich the citric acid cycle, experiments were performed to determine whether the addition of propionyl-L-carnitine (2 mM) can improve performance in working rat hearts utilizing acetoacetate (7.5 mM). Whereas the addition of propionyl-L-carnitine to acetoacetate resulted in a sustained improvement in the work output of the heart, the addition of propionate (2 mM) or L-carnitine (2 mM) alone to acetoacetate had negligible effects on contractile function. Propionyl-L-carnitine increased the uptake of acetoacetate by 130%, whereas beta-hydroxybutyrate release was minimal and unchanged compared with other groups. These observations show that rates of acetoacetate oxidation are increased commensurate with increased contractile function. Tissue metabolite data indicate that the utilization of propionyl-L-carnitine did not lead to accumulation of citric acid cycle intermediates in the span from citrate to 2-oxoglutarate but to an increase in the tissue content of malate. The results show that addition of propionyl-L-carnitine in hearts oxidizing acetoacetate results in improved mechanical performance that is comparable to the mechanical performance of hearts perfused with glucose as the only substrate. This improvement is most likely conferred by anaplerosis, as suggested by enhanced rates of acetoacetate utilization and citric acid flux.

Studies on the Citric Acid Cycle and its Portion of Glucose Breakdown by Calf and Bovine Lenses in vitro

1971 ◽  
Vol 2 (3-4) ◽  
pp. 143-148 ◽  
Author(s):  
O. Hockwin ◽  
G. Blum ◽  
I. Korte ◽  
T. Murata ◽  
W. Radetzki ◽  
...  
Keyword(s):  
Citric Acid ◽  
Citric Acid Cycle ◽  
Acid Cycle

scholarly journals Production of tricarballylic acid by rumen microorganisms and its potential toxicity in ruminant tissue metabolism

1986 ◽  
Vol 56 (1) ◽  
pp. 153-162 ◽  
Author(s):  
James B. Russell ◽  
Neil Forsberg
Keyword(s):  
Citric Acid ◽  
Citric Acid Cycle ◽  
Competitive Inhibitor ◽  
Rumen Microorganisms ◽  
Aconitate Hydratase ◽  
Factors Affecting ◽  
Acid Cycle ◽  
Rat Liver Cells ◽  
High Concentrations

1. Rumen microorganisms convert trans-aconitate to tricarballylate. The following experiments describe factors affecting the yield of tricarballylate, its absorption from the rumen into blood and its effect on mammalian citric acid cycle activity in vitro.2. When mixed rumen microorganisms were incubated in vitro with Timothy hay (Phleum praiense L.) and 6.7 mM-trans-aconitate, 64 % of the trans-aconitate was converted to tricarballylate. Chloroform and nirate treatments inhibited methane production and increased the yield of tricarballylate to 82 and 75% respectively.3. Sheep given gelatin capsules filled with 20 g trans-aconitate absorbed tricarballylate and the plasma concentration ranged from 0.3 to 0.5 mM 9 h after administration. Feeding an additional 40 g potassium chloride had little effect on plasma tricarballylate concentrations. Between 9 and 36 h there was a nearly linear decline in plasma tricarballylate.4. Tricarballylate was a competitive inhibitor of the enzyme, aconitate hydratase (aconitase; EC 4.2.1.3), and the inhibitor constant, KI, was 0.52 mM. This KIvalue was similar to the Michaelis-Menten constant (Km) of the enzyme for citrate.5. When liver slices from sheep were incubated with increasing concentrations of tricarballylate, [I4C]acetate oxidation decreased. However, even at relatively high concentrations (8 mM), oxidation was still greater than 80% of the maximum. Oxidation of [I4C]acetate by isolated rat liver cells was inhibited to a greater extent by tricarballylate. Concentrations as low as 0.5 mM caused a 30% inhibition of citric acid cycle activity.

scholarly journals Inhibition of Hypoxia-inducible Factor (HIF) Hydroxylases by Citric Acid Cycle Intermediates

2006 ◽  
Vol 282 (7) ◽  
pp. 4524-4532 ◽  
Author(s):  
Peppi Koivunen ◽  
Maija Hirsilä ◽  
Anne M. Remes ◽  
Ilmo E. Hassinen ◽  
Kari I. Kivirikko ◽  
...  
Keyword(s):  
Citric Acid ◽  
Transcriptional Activity ◽  
Citric Acid Cycle ◽  
Dimethyl Ester ◽  
Hypoxia Inducible Factor ◽  
Fumarate Hydratase ◽  
High Concentration ◽  
Cultured Fibroblasts ◽  
Acid Cycle

The stability and transcriptional activity of the hypoxia-inducible factors (HIFs) are regulated by two oxygen-dependent events that are catalyzed by three HIF prolyl 4-hydroxylases (HIF-P4Hs) and one HIF asparaginyl hydroxylase (FIH). We have studied possible links between metabolic pathways and HIF hydroxylases by analyzing the abilities of citric acid cycle intermediates to inhibit purified human HIF-P4Hs and FIH. Fumarate and succinate were identified as in vitro inhibitors of all three HIF-P4Hs, fumarate having Ki values of 50–80 μm and succinate 350–460 μm, whereas neither inhibited FIH. Oxaloacetate was an additional inhibitor of all three HIF-P4Hs with Ki values of 400–1000 μm and citrate of HIF-P4H-3, citrate being the most effective inhibitor of FIH with a Ki of 110 μm. Culturing of cells with fumarate diethyl or dimethyl ester, or a high concentration of monoethyl ester, stabilized HIF-1α and increased production of vascular endothelial growth factor and erythropoietin. Similar, although much smaller, changes were found in cultured fibroblasts from a patient with fumarate hydratase (FH) deficiency and upon silencing FH using small interfering RNA. No such effects were seen upon culturing of cells with succinate diethyl or dimethyl ester. As FIH was not inhibited by fumarate, our data indicate that the transcriptional activity of HIF is quite high even when binding of the coactivator p300 is prevented. Our data also support recent suggestions that the increased fumarate and succinate levels present in the FH and succinate dehydrogenase-deficient tumors, respectively, can inhibit the HIF-P4Hs with consequent stabilization of HIF-αs and effects on tumor pathology.

scholarly journals Dipropionylcysteine Ethyl Ester Compensates for Loss of Citric Acid Cycle Intermediates During Post Ischemia Reperfusion in the Pig Heart

2009 ◽  
Vol 23 (6) ◽  
pp. 459-469 ◽  
Author(s):  
Takhar Kasumov ◽  
Naveen Sharma ◽  
Hazel Huang ◽  
Rajan S. Kombu ◽  
Andrea Cendrowski ◽  
...  
Keyword(s):  
Citric Acid ◽  
Ethyl Ester ◽  
Citric Acid Cycle ◽  
Ischemia Reperfusion ◽  
Acid Cycle

scholarly journals Triiodothyronine increases myocardial function and pyruvate entry into the citric acid cycle after reperfusion in a model of infant cardiopulmonary bypass

2012 ◽  
Vol 302 (5) ◽  
pp. H1086-H1093 ◽  
Author(s):  
Aaron K. Olson ◽  
Bertrand Bouchard ◽  
Xue-Han Ning ◽  
Nancy Isern ◽  
Christine Des Rosiers ◽  
...  
Keyword(s):  
Cardiopulmonary Bypass ◽  
Citric Acid ◽  
Cardiac Function ◽  
Citric Acid Cycle ◽  
Ischemia Reperfusion ◽  
Resonance Spectroscopy ◽  
Acid Cycle ◽  
Neonatal Piglets ◽  
Group I ◽  
Molar Percent

Triiodothyronine (T3) supplementation improves clinical outcomes in infants after cardiac surgery using cardiopulmonary bypass by unknown mechanisms. We utilized a translational model of infant cardiopulmonary bypass to test the hypothesis that T3 modulates pyruvate entry into the citric acid cycle (CAC), thereby providing the energy support for improved cardiac function after ischemia-reperfusion (I/R). Neonatal piglets received intracoronary [2-13Carbon(13C)]pyruvate for 40 min (8 mM) during control aerobic conditions (control) or immediately after reperfusion (I/R) from global hypothermic ischemia. A third group (I/R-Tr) received T3 (1.2 μg/kg) during reperfusion. We assessed absolute CAC intermediate levels and flux parameters into the CAC through oxidative pyruvate decarboxylation (PDC) and anaplerotic carboxylation (PC) using [2-13C]pyruvate and isotopomer analysis by gas and liquid chromatography-mass spectrometry and 13C-nuclear magnetic resonance spectroscopy. When compared with I/R, T3 (group I/R-Tr) increased cardiac power and oxygen consumption after I/R while elevating flux of both PDC and PC (∼4-fold). Although neither I/R nor I/R-Tr modified absolute CAC levels, T3 inhibited I/R-induced reductions in their molar percent enrichment. Furthermore, 13C-labeling of CAC intermediates suggests that T3 may decrease entry of unlabeled carbons at the level of oxaloacetate through anaplerosis or exchange reaction with asparate. T3 markedly enhances PC and PDC fluxes, thereby providing potential substrate for elevated cardiac function after reperfusion. This T3-induced increase in pyruvate fluxes occurs with preservation of the CAC intermediate pool. Our labeling data raise the possibility that T3 reduces reliance on amino acids for anaplerosis after reperfusion.

scholarly journals Dipropionylcysteine ethyl ester compensates for the leakage of citric acid cycle intermediates in the pig heart with ischemia/reperfusion.

2006 ◽  
Vol 20 (5) ◽  
Author(s):  
Takhar Kasumov ◽  
Naveen Sharma ◽  
Hazel Huang ◽  
Katherine Thomas ◽  
Henri Brunengraber ◽  
...  
Keyword(s):  
Citric Acid ◽  
Ethyl Ester ◽  
Citric Acid Cycle ◽  
Ischemia Reperfusion ◽  
Acid Cycle
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