Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: KEGG:D00037 (citric acid)
9,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To identify the effect of L-propionylcarnitine (LPC) on ischemia, 31 fasting, untreated male patients with left coronary artery disease were studied during 2 identical pacing stress tests 45 minutes before (atrial pacing test I [APST I]) and 15 minutes after (APST II) administration of 15 mg/kg of LPC or placebo. Hemodynamic, metabolic, and nuclear angiographic variables were studied before, during, and for 10 minutes after pacing. After LPC administration, arterial total carnitine levels increased from 47 +/- 1.7 mumol/liter (control) to 730 +/- 30 mumol/liter. Hemodynamic and metabolic variables were comparable in LPC and placebo during APSI I, and reproducible in placebo during both tests. Although LPC did not affect myocardial oxygen demand and supply, it diminished myocardial ischemia, indicated by a significant 12% and 50% reduction in ST-segment depression and left ventricular end-diastolic pressure, respectively, during APST II. Moreover, during APST II, left ventricular ejection fraction increased by 18% (p < 0.05 vs APST I). Furthermore, LPC improved recovery of myocardial function after pacing, with a reduction in the time to peak filling and a 21% increase in both peak ejection and filling rates 10 minutes after pacing (all p < 0.05). Thus, LPC prevents ischemia-induced ventricular dysfunction, not by affecting the myocardial oxygen supply-demand ratio but as a result of its intrinsic metabolic actions, increasing pyruvate dehydrogenase activity and flux through the citric acid cycle. Because it is well tolerated, it may be a valuable alternative or addition to available antiischemic therapy.
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PMID:Effects of L-propionylcarnitine on ischemia-induced myocardial dysfunction in men with angina pectoris. 802 75

Functional recovery following ischemia and reperfusion in the isolated working rat heart perfused with glucose (11 mM) was examined in relation to pre- and postischemic levels of ATP, glycogen, glucose 6-phosphate, and the lactate-to-pyruvate ratio. The following variables were studied: feeding and fasting in vivo, addition of L-lactate (10 mM), dl-beta-hydroxybutyrate (10 mM), glucagon (0.01 and 1 micrograms/ml), and a 15-min anoxic perfusion before ischemia in vitro. Recovery was assessed as the percentage of preischemic power. Good correlation was found between functional recovery and the postischemic content of glycogen. Glycogen depletion by anoxia or glucagon before ischemia impaired recovery. There was no relationship among lactate produced, or the lactate-to-pyruvate ratio, and recovery. The addition of lactate or beta-hydroxybutyrate to hearts from fed rats increased the content of glycogen and glucose 6-phosphate, whereas addition of lactate, but not beta-hydroxybutyrate, improved recovery. There was a linear relationship between glycogen content and glucose 6-phosphate levels. In conclusion, the degree of return of oxidative metabolism and of net glycogen resynthesis reflects postischemic recovery of function. The results also suggest a role for anaplerosis of the citric acid cycle as an additional determinant of postischemic recovery.
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PMID:Metabolic recovery of isolated working rat heart after brief global ischemia. 806 97

The effect of aspartate and glutamate on myocardial function during reperfusion is controversial. A beneficial effect has been attributed to altered delivery of carbon into the citric acid cycle via substrate oxidation or by stimulation of anaplerosis, but these hypotheses have not been directly tested. 13C isotopomer analysis is well suited to the study of myocardial metabolism, particularly where isotopic and metabolic steady state cannot be established. This technique was used to evaluate the effects of aspartate and glutamate (amino acids, AA) on anaplerosis and substrate selection in the isolated rat heart after 25 min of ischemia followed by 30 or 45 min of reperfusion. Five groups of hearts (n = 8) provided with a mixture of [1,2-13C]acetate, [3-13C]lactate, and unlabeled glucose were studied: control, control plus AA, ischemia followed by 30 min of reperfusion, ischemia plus AA followed by 30 min of reperfusion, and ischemia followed by 45 min of reperfusion. The contribution of lactate to acetyl-CoA was decreased in postischemic myocardium (with a significant increase in acetate), and anaplerosis was stimulated. Metabolism of 13C-labeled aspartate or glutamate could not be detected, however, and there was no effect of AA on functional recovery, substrate selection, or anaplerosis. Thus, in contrast to earlier reports, aspartate and glutamate have no effect on either functional recovery from ischemia or on metabolic pathways feeding the citric acid cycle.
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PMID:Effects of amino acids on substrate selection, anaplerosis, and left ventricular function in the ischemic reperfused rat heart. 810 82

A new 13C NMR technique for measuring substrate utilization by the citric acid cycle based on an analysis of succinate 13C isotopomers is presented. The relative contribution of up to three different labeling patterns in acetyl-CoA entering the citric acid cycle may be determined under non-steady-state conditions. We present experimental data from perfused rat hearts subjected to a brief period of ischemia, where both succinate and glutamate resonances were observed in the 13C spectrum. The contributions of labeled exogenous acetate and lactate and unlabeled sources to the acetyl-CoA pool were compared using this succinate analysis and a previously published glutamate analysis [Malloy et al. (1990) Biochemistry 29, 6756-6761], and the two methods give identical results. This indicates that the succinate and glutamate isotopomers originated from a common alpha-ketoglutarate pool, verifying that glutamate is in isotopomeric equilibrium with alpha-ketoglutarate under these conditions.
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PMID:Sources of acetyl-CoA entering the tricarboxylic acid cycle as determined by analysis of succinate 13C isotopomers. 821 1

We monitored chronically (for 1 week) the effect of the 21-aminosteroid U74006F, a potent lipid peroxidation inhibitor, on the pH profile of the rat brain following transient forebrain ischemia. Eight rats were treated initially with 3 mg/kg i.v. of U74006F 1 min after reperfusion. A second dose of 1.5 mg/kg i.v. was given 60 min after reperfusion. A vehicle group (n = 9) was treated in the same manner, using the same volume of the vehicle solution, 20 mM citric acid, 3 mM sodium citrate, and 8 mM NaCl. Statistically significant interaction between group and time (P = 0.003) was detected for pH. Brain pH of the vehicle treated animals were significantly higher than the U74006F treated group at 24 h (P = 0.009) and 48 h (P = 0.009) of reperfusion. Chronic post-ischemic brain tissue alkalosis at 24 h (pH 7.22 +/- 0.12) and 48 h (pH 7.25 +/- 0.11) post-ischemia, observed among the vehicle treated animals (and untreated animals), was suppressed by treatment with U74006F. These results suggest a coupling between post-ischemic brain tissue alkalosis and free radical induced lipid peroxidation.
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PMID:Post-ischemic brain tissue alkalosis suppressed by U74006F. 843 95

DL-1,3-butanediol (DL-BD) is an ethanol dimer which affords cerebral protection in various experimental models of hypoxia and ischemia but its mechanism of action is unknown. DL-BD is a ketogenic alcohol and it has been proposed that its protective effect was accomplished through cerebral utilization of ketone bodies. Since DL-BD is a racemic, its metabolic effects could be due to D, L or both isomers. The effects of equimolar doses of DL-, D- and L-BD (25 mmol/Kg) on cerebral metabolism were studied by measuring the cortical levels of the main glycolytic (glycogen, glucose, glucose 6-phosphate, fructose 1,6-diphosphate, pyruvate and lactate) and citric acid cycle (citrate, alpha-ketoglutarate and L-malate) intermediates. The two BD isomers exerted different effects on cerebral metabolism. Unlike L-BD, D- and DL-BD treatments resulted in a slight (+10%) but significant increase in citrate level whereas L-BD treatment led to significant reduction in pyruvate (-12%) and lactate (-24%) levels. These effects were apparently not linked to hyperketonemia, since DL-BHB treatment, which mimicked hyperketonemia induced by DL-BD, had no effect on cerebral metabolites but might be due to intracerebral metabolism of BD.
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PMID:Effect of D- and L-1,3-butanediol isomers on glycolytic and citric acid cycle intermediates in the rat brain. 884 93

Cardioplegic solutions rich in the hydrophilic, basic amino acids, glutamate and aspartate, have enhanced myocardial preservation and left ventricular function. This has been demonstrated in assorted animal preparations involving ischemia with and without reperfusion. Published clinical data, though limited, strongly support the contention that these amino acids have myocardial protective properties. Several biochemical mechanisms exist by which certain amino acids may attenuate ischemic or reperfusion injury. Glutamate and aspartate may become preferred myocardial fuels in the setting of ischemia. They may also reduce myocardial ammonia production and reduce cytoplasmic lactate levels, thereby deinhibiting glycolysis. Some amino acids may become substrate for the citric acid cycle. Glutamate and aspartate also move reducing equivalents from cytoplasm to mitochondria where they are necessary for oxidative phosphorylation and energy generation. A rationale exists for the use of an amino acid-rich cardioplegia-like solution in myocardial infarction. These solutions are safe and inexpensive.
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PMID:Potential cardiovascular applications of glutamate, aspartate, and other amino acids. 975 77

Kidney proximal tubule cells developed severe energy deficits during hypoxia/reoxygenation not attributable to cellular disruption, lack of purine precursors, the mitochondrial permeability transition, or loss of cytochrome c. Reoxygenated cells showed decreased respiration with complex I substrates, but minimal or no impairment with electron donors at complexes II and IV. This was accompanied by diminished mitochondrial membrane potential (DeltaPsi(m)). The energy deficit, respiratory inhibition, and loss of DeltaPsi(m) were strongly ameliorated by provision of alpha-ketoglutarate plus aspartate (alphaKG/ASP) supplements during either hypoxia or only during reoxygenation. Measurements of (13)C-labeled metabolites in [3-(13)C]aspartate-treated cells indicated the operation of anaerobic pathways of alphaKG/ASP metabolism to generate ATP, yielding succinate as end product. Anaerobic metabolism of alphaKG/ASP also mitigated the loss of DeltaPsi(m) that occurred during hypoxia before reoxygenation. Rotenone, but not antimycin or oligomycin, prevented this effect, indicating that electron transport in complex I, rather than F(1)F(0)-ATPase activity, had been responsible for maintenance of DeltaPsi(m) by the substrates. Thus, tubule cells subjected to hypoxia/reoxygenation can have persistent energy deficits associated with complex I dysfunction for substantial periods of time before onset of the mitochondrial permeability transition and/or loss of cytochrome c. The lesion can be prevented or reversed by citric acid cycle metabolites that anaerobically generate ATP by intramitochondrial substrate-level phosphorylation and maintain DeltaPsi(m) via electron transport in complex I. Utilization of these anaerobic pathways of mitochondrial energy metabolism known to be present in other mammalian tissues may provide strategies to limit mitochondrial dysfunction and allow cellular repair before the onset of irreversible injury by ischemia or hypoxia.
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PMID:Mitochondrial dysfunction during hypoxia/reoxygenation and its correction by anaerobic metabolism of citric acid cycle intermediates. 1071 1

It is well established that myocardial blood flow is heterogeneous on the local level. During recent years comprehensive studies have been undertaken to assess the relation between myocardial metabolism and spatial blood flow heterogeneity. Based on the type of measurements two major groups of studies have been performed: enzyme activity and tissue metabolite level assessments. Enzyme activity measurements have provided only limited insight into the coupling of local metabolism and flow. This is probably due to the fact that, in addition to estimated Vmax values, local substrate affinity (Km values) and substrate concentrations affect the metabolite fluxes. However, the latter two variables remain normally unknown. In contrast, valuable insight has been obtained concerning flow-metabolism matching from tissue metabolite measurements, especially when connected with mathematical model analyses. The latter permitted the calculation of metabolic flux rates (e.g., production of oxidation water, citric acid cycle flux, glucose uptake, fatty acid uptake) or the translation of the metabolic indexes into physiologically meaningful local metabolite concentrations (e.g., free cytosolic adenosine). The bottom line of the studies reported to date is that the broad range of myocardial flows observed under resting control conditions correlates with local metabolism possibly affected by spatial differences in adrenergic stimulation. Thus, high flow samples exhibit a higher oxidative metabolism than low flow samples. As a result the flow threshold below which local myocardial ischemia ensues is higher in control high flow samples. The importance of these findings with respect to local flow-metabolism matching is underlined by the finding that the probability of developing an infarction following ischemia/reperfusion is related to the functional state of the myocardium under control conditions, i.e., the local level of flow-metabolism matching.
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PMID:Heterogeneity of metabolic parameters in the left ventricular myocardium and its relation to local blood flow. 1177 75

Within the left ventricular myocardium, substantial differences can be observed in terms of both perfusion and energy turnover. In addition to the small transmural gradient from the subepi--to the subendocardium (1:1.2), more recent high-resolution studies reveal a major patchwork-pattern, e.g., in terms of flow. Adjacent 200 microliters areas can differ more than 3-fold in local perfusion. Low flow and high flow areas (< 50% or > 150% of mean flow, respectively) represent up to 1/5 of the left ventricular myocardium. This local flow pattern is temporally stable for at least days and possibly weeks. Low and high flow areas also differ in local energy metabolism. High flow areas are characterized by enhanced glucose phosphorylation and fatty acid permeability, resulting in increased uptake of these substrates. This is the basis for the recent finding that high flow areas are characterized by an enhanced turnover of the citric acid cycle and thus of local O2 consumption. Since local O2 supply and consumption are closely coupled, low flow areas display no biochemical signs of ischemia. Reducing local flow by 50% results in a similar rise of adenosine or lactate in low and high flow areas. Following complete cessation of perfusion, high flow areas display a greater risk of infarction, indicating enhanced energy demand. Further studies are needed to elucidate the molecular basis of this spatial heterogeneity and to test whether the 3-fold differences in local energy turnover within the myocardial wall also translate into comparable variations of local contractility.
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PMID:[Spatial heterogeneity of myocardial circulation and energy metabolism]. 1182 39


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