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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bioenergetic and hemodynamic consequences of cellular redox manipulations by 0.2-20 mM pyruvate were compared with those due to adrenergic stress (0.7-1.1 microM norepinephrine) using isolated working guinea-pig hearts under the conditions of normoxia, low-flow ischemia, and reperfusion. 5 mM glucose (+ 5 U/l insulin) + 5 mM lactate were the basal energy-yielding substrates. To stabilize left ventricular enddiastolic pressure, ventricular filling pressure was held at 12 cmH2O under all conditions; this preload control minimized Frank-Starling effects on ventricular inotropism. Global low-flow ischemia was induced by reducing aortic pressure to levels (20-10 cmH2O) below the coronary autoregulatory reserve. Reactants of the creatine kinase, including H+ and other key metabolites, were measured by enzymatic, HPLC, and polarographic techniques. In normoxic hearts, norepinephrine stimulations of inotropism, heart rate x pressure product, and oxygen consumption (MVO2) were associated with a fall in the cytosolic phosphorylation potential [( ATP]/[( ADP].[Pi]] as judged by the creatine kinase equilibrium. In contrast, infusion of excess pyruvate (5 mM) markedly increased [ATP]/[( ADP].[Pi]) and ventricular work output, while intracellular phosphate decreased; MVO2 remained constant under the same conditions. During reperfusion following ischemia, pyruvate effected striking and concentration-dependent increases in MVO2, phosphorylation potential, and inotropism. Pyruvate dehydrogenase flux was augmented during reperfusion hyperemia followed by near-complete recoveries of [ATP]/([ADP].[Pi]), contractile force, heart rate x pressure product, and MVO2 in the presence of 5-10 mM pyruvate. Pyruvate also attenuated ischemic adenylate degradation. Omission of glucose from the perfusion medium rendered pyruvate ineffective in postischemic hearts. Similarly, excess lactate (5-15 mM) or acetate (5 mM) failed to reenergize reperfused hearts and severe depressions of MVO2 and inotropism developed despite the presence of glucose. Apparently, subcellular redox manipulations by pyruvate dissociated stimulated mitochondrial respiration and increased inotropism from low cytosolic phosphorylation potentials. This was evidence against the extramitochondrial [ADP].[Pi]/[ATP] ratio being the primary factor in the control of mitochondrial respiration. The mechanism of pyruvate enhancement of inotropism during normoxia and reperfusion is probably multifactorial. Thermodynamic effects on subcellular [NADH]/[NAD+] ratios are coupled with a rise in the cytosolic [ATP]/[( ADP].[Pi]) ratio at constant (normoxia) or increased (reperfusion) MVO2.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pyruvate-enhanced phosphorylation potential and inotropism in normoxic and postischemic isolated working heart. Near-complete prevention of reperfusion contractile failure. 270 62

We studied lipolysis in the isolated rat heart, measured as glycerol release during anoxia, low-flow ischemia and subsequent reperfusion. It was found that the rate of lipolysis was enhanced during ischemia/anoxia while the lipase activities in tissue extracts involved in the myocardial lipolysis and the amount of triglycerides were not affected. This indicates the dominant occurrence of a lipolysis-reesterification principle in ischemic and anoxic tissue. A common observation of ischemia/anoxia is an increase in the tissue NADH/NAD+ ratio. Therefore we investigated the effect of lactate and malate, both of which enhance the tissue redox state on myocardial lipolysis. Perfusion in the presence of lactate (10 mM) and malate (10 mM) both stimulated myocardial lipolysis by about five times. This suggests that the rate of reesterification of product fatty acids to triglycerides, which is determined by the NADH/NAD+ ratio, because of the increased formation of glycerol 3-phosphate from dihydroxy acetone phosphate, plays an important role in the regulation of lipolysis. The existence of triglyceride-fatty acid-triglyceride cycle is discussed.
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PMID:Enhanced lipolysis of myocardial triglycerides during low-flow ischemia and anoxia in the isolated rat heart. 273 May 23

Thirty minutes of warm hepatic ischemia produced by portal triad cross-clamping was repeated five times at 30-minute intervals in three groups of five dogs each: Group A was subjected only to portal triad cross-clamping; Group B received simultaneous clamping of the celiac axis and the superior mesenteric artery; and Group C had a simultaneous splenojugular shunt. The arterial blood ketone body ratio (acetoacetate/beta-hydroxybutyrate: KBR), reflecting the NAD+/NADH ratio in liver mitochondria, decreased significantly after each cross-clamping in all groups. After the first declamping, there was no significant difference in the recovery rate of the KBR among the three groups. After the second declamping, the recovery rate in Group A decreased significantly compared with the rates of Groups B and C (P less than 0.05). After the fourth declamping, the recovery rate in Group B was significantly lower than that of Group C (P less than 0.05). The hepatic energy charge [(ATP + 1/2ADP)/(ATP + ADP + AMP)] 30 minutes after the fifth declamping decreased significantly to 0.75 +/- 0.01 in Group A, compared with 0.84 +/- 0.01 in Group C (P less than 0.01). The lactate and total free plasma amino acid levels in the arterial blood increased significantly in the order of Groups A, B, and C. It is suggested that the inflow of stagnant portal venous blood to ischemic liver impairs hepatic energy metabolism.
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PMID:Deleterious effects of splanchnic congestion on hepatic energy metabolism following repeated portal triad cross-clamping in dogs. 319 65

The enzyme xanthine: acceptor oxidoreductase found in rat heart equilibrates between three forms differing in electron acceptor specificity. Form D transfers electrons exclusively to NAD+ and accounts for 85% of total oxidoreductase activity. Form O transfers electrons to molecular oxygen and accounts for 8%. The D/O form prefers NAD+, but without NAD+ transfers electrons to oxygen. Interconversion from D to O and O to D forms is catalyzed by sulfhydryl group-modifying reagents: Cd2+, Cu2+, disulfiram, and heating with dithiothreitol. This suggests that sulfhydryl groups participate in the first stage of enzyme conversion. The NADH/NAD+ concentration ratio may regulate the dehydrogenase activity of xanthine:acceptor oxidoreductase (NAD+-dependent activity of D and D/O forms). Accumulating NADH inhibits hypoxanthine hydroxylation. The amount of form O increases during cardiac ischemia, facilitating superoxide radical-ion generation. Also, NADH/NAD+ does not regulate form O, promoting adenylate nucleotide pool depletion, especially in the heart which has low de novo purine nucleotide synthesis.
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PMID:Three forms of xanthine: acceptor oxidoreductase in rat heart. 346 36

Brain levels of NADH and NAD+ were measured in three models of cerebral ischemia to determine whether degradation of the pyridine nucleotides is enhanced in models that generate high concentrations of lactic acid. Complete ischemia (decapitation), in which lactate increased to 14 mmol/kg, caused a gradual decrease in the NAD pool to 50% of control by 2 h. During focal ischemia (occlusion of the middle cerebral artery), the decrease in the NAD pool was less pronounced (82% of control at 2 h) despite the accentuated accumulation of lactate to 33 mmol/kg. In a third model (unilateral hypoxia-ischemia), pretreatment of animals with glucose augmented the ischemic elevation of lactate from 30 mmol/kg to 40 mmol/kg and greatly impaired restoration of energy metabolites during recirculation. However, glucose pretreatment had no effect on the size of the NAD pool during ischemia or early recovery. These results, therefore, demonstrate that the pyridine nucleotide pool is not rapidly degraded during ischemic insults that accumulate high concentrations of lactic acid. The stability of the NAD pool may have been enhanced by the limited increase in brain levels of NADH that occurred in these models of incomplete ischemia.
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PMID:Effect of lactacidosis on pyridine nucleotide stability during ischemia in mouse brain. 361 29

Cerebral ischemia was induced in cats using bilateral carotid artery occlusion coupled with hemorrhagic hypotension. Thirty minutes of ischemia, which depleted levels of ATP and phosphocreatine throughout the cerebral cortex, was followed by 2-4 hours of recirculation. During the recovery period, cortical perfusion and NADH fluorescence were monitored through a cranial window. Postischemic perfusion, as indicated by transit time, was initially higher than control, but declined to subnormal levels by 60 minutes. NADH fluorescence transients, induced by brief anoxia, also decreased steadily during recirculation, indicating a failure of oxidation-reduction capability. The disappearance of anoxic-NADH transients usually preceded the decline of flow, suggesting that O2 delivery was not the factor limiting redox reactions. Furthermore, tissue levels of NADH, which were nearly normal after 2-4 hours of recirculation, did not indicate tissue hypoxia. In spite of normalization of NADH, resynthesis of high energy phosphates were severely impaired. The degree of ATP recovery varied widely in different cortical regions; however, there were two general groups of ATP values--one at 5% and the other at 70% of control levels. In the energy-depleted areas, NADH levels were normal, but the total pool of NAD (NADH + NAD+) and the tissue content of K+ were 43% lower than control. In contrast, the NAD pool and K+ content were only slightly diminished in the regions with greater ATP restitution. The results suggest that postischemic resynthesis of ATP may be limited not by inadequate delivery of O2, but rather by defective production of NADH.
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PMID:Factors limiting regeneration of ATP following temporary ischemia in cat brain. 706 95

Glycerin-3-P, commonly known as alpha-glycerophosphate and dihydroxyacetone phosphate (DHAP) were measured in well defined microscopic samples of the simple liver acinus allowing a comparison of the glycerin-3-P/dihydroxyacetone-P-ratios of Zones 1 and 3 as a measure of the free NAD+/NADH ratio. The ATP/ADP X Pi quotients were determined in these same microscopic areas of the liver acinus as a measure of the phosphate potential. Brief ischemia was used to disturb the system. The results indicate that the oxidation-reduction and phosphate potentials are uniform throughout the entire liver lobule.
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PMID:Quantitative histochemical resolution of the oxidation-reduction and phosphate potentials within the simple hepatic acinus. 706 1

Purine and pyrimidine nucleotides are essential energy sources for basic metabolic reactions and play important roles in protein, glycogen, and nucleic acid synthesis, cyclic nucleotide metabolism, and energy transfer reactions. Brief coronary occlusions (12 min) were produced in seven open-chest dogs, and repetitive myocardial samples were taken in order to determine the response of the nucleotide pool to ischemia and reperfusion. During ischemia adenosine 5'-triphosphate (ATP) decreased to 57% of control, and similar decreases occurred in the guanosine 5'-triphosphate (GTP), cytidine 5'-triphosphate (CTP), uridine 5'-triphosphate (UTP), and nicotinamide adenine dinucleotide (NAD+) pools. The decrease in nucleotides was accompanied by an increase in nucleosides and bases. After 60 min of reperfusion the content of all nucleotides had increased but was still significantly less than nonischemic values. The content of nucleosides and bases decreased immediately upon reperfusion. In contrast, creatine phosphate (CP) fell to 10% of control during ischemia but rebounded to above control values immediately upon reperfusion. Thus depletion of all nucleotide pools occurs during ischemia, and with reperfusion nucleotide content is restored only slowly. Delayed repletion is not caused by a defect in mitochondrial synthesis of ATP because CP content is restored rapidly. The slow repletion of nucleotides may be secondary to loss of nucleotide precursors during reperfusion and may result in widespread alterations in myocardial metabolism.
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PMID:Prolonged myocardial nucleotide depletion after brief ischemia in the open-chest dog. 708 54

Xanthine oxidase and xanthine dehydrogenase are enzymes involved in the metabolism of purines and pyrimidines in various organisms. Their relationship to one another has been the subject of considerable debate, primarily because of their proposed roles in ischemia/reperfusion damage in tissues. Differences in the kinetics and oxidation-reduction behavior of the two forms are accounted for by the presence in the dehydrogenase of a binding site for NAD+, as well as a substantially lower reduction potential for the flavin FADH./FADH2 couple of the dehydrogenase relative to the oxidase. This review presents recent advances of our understanding of the biochemistry and molecular biology of these systems, including a model for the overall morphology of xanthine oxidizing enzymes. The evidence that the two enzymes represent alternate forms of the same gene product, in some cases reversibly interconvertible between one another, is discussed.
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PMID:Flavoprotein structure and mechanism. 4. Xanthine oxidase and xanthine dehydrogenase. 764 15

Reactive oxygen species (ROS) generated from xanthine oxidase (XO) play an important role in ischemia-induced injury. We hypothesize that XO and xanthine dehydrogenase (XDH) are released into the circulation with ischemia reperfusion to the human liver and intestine. Blood was drawn from a patient, before and at intervals after an aortic cross-clamp procedure. Plasma was incubated in the presence of xanthine, with NAD+ (for XD +XO) and without NAD+ (for XO). The amount of urate formed was quantified using a high-performance liquid chromatograph (HPLC). The calculated XDH+XO and XO activity increased from 1.88 and 1.66 microU/mg protein, respectively, before the cross clamp to 3.77 and 3.11 microU/mg, respectively, 7 minutes after reperfusion to the superior mesenteric, celiac, and right renal artery beds. The release of a significant biological source of ROS may explain the damage to lung or heart observed after ischemia to the human liver and intestine.
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PMID:Circulating xanthine oxidase in human ischemia reperfusion. 771 6


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