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

High levels of fatty acids decrease the extent of mechanical recovery of hearts reperfused following a transient period of severe ischemia. Glucose oxidation rates during reperfusion are low under these conditions, which can result in a decreased recovery of mechanical function. Stimulation of glucose oxidation with the carnitine palmitoyl transferase I inhibitor, Etomoxir, or by directly stimulating pyruvate dehydrogenase activity with dichloroacetate (DCA) results in an improvement in mechanical function during reperfusion of previously ischemic hearts. Addition of DCA (1 mM) to hearts perfused with 11 mM glucose and 1.2 mM palmitate results in an increase in contribution of glucose oxidation to overall ATP production from 6 to 23%, with a parallel decrease in that of fatty acid oxidation from 90 to 69%. In aerobic hearts, endogenous myocardial triglycerides are an important source of fatty acids for beta-oxidation. Using hearts in which the myocardial triglycerides were pre-labeled, the contribution of both endogenous and exogenous fatty acid oxidation to myocardial ATP production was determined in hearts perfused with 11 mM glucose, 1.2 mM palmitate and 500 microU/ml insulin. In hearts reperfused following a 30 min period of global no flow ischemia, 91.9% of ATP production was derived from endogenous and exogenous fatty acid oxidation, compared to 87.7% in aerobic hearts. This demonstrates that fatty acid oxidation quickly recovers following a transient period of severe ischemia. Furthermore, therapy aimed at overcoming fatty acid inhibition of glucose oxidation during reperfusion of ischemic hearts appears to be beneficial to recovery of mechanical function.
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PMID:The relative contribution of glucose and fatty acids to ATP production in hearts reperfused following ischemia. 148 Jan 39

The hypothesis that substrate availability can alter contractile function in reperfused myocardium after global ischemia was investigated in this study. Isolated rabbit hearts were placed in a dual tuned (31P/13C) NMR probe with a 9.4-T magnet and perfused with the following substrates given individually or in combination: 10 mM glucose, 2 mM palmitate, and 2.5 mM [3-13C]pyruvate. Glucose was the sole substrate present for all groups of hearts before the onset of 10 or 20 minutes of zero-flow ischemia. Contractility (dP/dt) was significantly higher in hearts reperfused with glucose compared with hearts reperfused with palmitate or the combination. In addition, myocardial oxygen consumption/unit of work at reperfusion was more efficient with glucose than with palmitate. ATP content during reperfusion was similar with glucose and palmitate and did not account for improved function with glucose. To determine if inhibition of pyruvate metabolism by palmitate might result in altered postischemic function, additional hearts were reperfused with 2.5 mM [3-13C]pyruvate provided alone or in combination with palmitate. Using 13C NMR spectroscopy, it was shown that with the addition of palmitate, pyruvate oxidation was decreased in control and 10-minute ischemic hearts as is consistent with inhibition of pyruvate dehydrogenase by fatty acids. However, palmitate/pyruvate did not worsen postischemic function as compared with palmitate or pyruvate alone. Tricarboxylic acid cycle activity was slowed in reperfused pyruvate hearts, but no further reduction was observed when palmitate was present. In conclusion, palmitate reduces the mechanical function of the reperfused isolated rabbit heart as compared with glucose. This effect of palmitate does not appear to be caused by suppression of pyruvate oxidation or by a change in high energy phosphate content.
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PMID:Fatty acid metabolism and contractile function in the reperfused myocardium. Multinuclear NMR studies of isolated rabbit hearts. 174 64

High levels of tissue lactate exacerbate tissue damage that results from cerebral ischemia and reperfusion injury that follows. Post-ischemic treatment with dichloroacetate (DCA) facilitates a decrease in lactate in the central nervous system (CNS) of animals during reperfusion following experimental ischemia, thus it may help to ameliorate ischemic cell damage. It has been suggested that the lactate lowering effect is mediated through a stimulatory effect of DCA on pyruvate dehydrogenase (PDHC) activity. We have studied such a hypothesis in a human astrocytoma derived cell line, UC-11MG. Under conditions resembling those of the ischemic tissue (i.e. high lactate and low pH) these cells accumulate lactate, driven by the inwardly directed proton gradient, and swell as a consequence of the osmotic effect of intracellular lactate. We have demonstrated that DCA increases PDHC activity and also reduces lactate-induced swelling. However, we also found that these two effects could be uncoupled and that the ability of DCA to prevent swelling is still present in the absence of any stimulation of PDHC. We also demonstrated that DCA competitively inhibits the uptake of lactate (Ki = 1.9 mM) and increases the efflux of lactate in a trans-acting manner that suggests the presence of a lactate-DCA exchange. We present a mechanism by which reduction in the rate of lactate uptake could account for the observed inhibition of swelling. This effect of DCA on lactate transport indicates another possible mechanism of action for DCA in facilitating the decrease in lactate observed in vivo during reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of lactate-induced swelling by dichloroacetate in human astrocytoma cells. 181 83

The effects of physiologic and pharmacologic manipulations on contact lens-induced edema were studied. In isolated superfused rabbit corneas bathed in Ringer's solution and covered with large-diameter polymethylmethacrylate (PMMA) lenses, corneal swelling rates of 17-26 microns/hr (versus -5-5 microns/hr in paired controls) were observed. Neither the calcium antagonist diltiazem (10(-4) M), the glucocorticoid dexamethasone (10(-7) M), the glucose substitute fructose (20 mM), nor 0.5 mM adenosine and 0.3 mM reduced glutathione mitigated the edema. Lens-induced edema was 25 microns/hr in corneas bathed at pH 8.2 and decreased to 9 microns/hr at pH 7.0. In corneas without lenses, however, decreasing the pH from 7.4-7.0 caused significant swelling (P less than 0.05). The pyruvate dehydrogenase stimulant sodium dichloroacetate (3.2 mM) on the tears side ameliorated the edema, and its congener, 3.2 mM 2-chloropropionate, was less effective. These latter agents are known to relieve lactic acidosis systemically and had no significant effect on corneas without lenses. In tissues bathed with 20 mM lactate Ringer's, normal thickness was maintained in both control and PMMA-treated corneas throughout the 3-hr period. These findings suggest that the contact lens-induced edema does not involve the acute cytotoxic mechanisms seen in severe tissue ischemia or hypoxia. The edema appears to result in part from acidosis but mainly from stromal lactate accumulation.
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PMID:Contact lens-induced edema in vitro. Pharmacology and metabolic considerations. 199 86

The present study was undertaken to examine whether dichloroacetate, which inhibits pyruvate dehydrogenase kinase and, therefore, increases the activity of pyruvate dehydrogenase, attenuates myocardial acidosis and metabolic changes induced by coronary occlusion. In dogs anesthetized with pentobarbital, the left anterior descending coronary artery was incompletely occluded to reduce the left anterior descending flow to a half to one third of the original flow (partial occlusion) to produce myocardial (regional) ischemia. Partial occlusion was continued for 90 min, and a bolus injection of saline or dichloroacetate was made intravenously 30 min after the onset of occlusion. Partial occlusion decreased myocardial pH significantly. An injection of dichloroacetate (150 mg/kg) increased myocardial pH that had been lowered by partial occlusion. Myocardial metabolites were measured in other dogs. Partial occlusion decreased the myocardial levels of adenosine triphosphate, creatine phosphate and energy charge potential, and increased that of lactate significantly, without affecting the myocardial levels of pyruvate and nonesterified fatty acids. Dichloroacetate attenuated the ischemia-induced changes in the myocardial levels of adenosine triphosphate, creatine phosphate, energy charge potential and lactate. These results indicate that dichloroacetate attenuates the myocardial acidosis and metabolic changes during coronary partial occlusion.
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PMID:Dichloroacetate attenuates myocardial acidosis and metabolic changes induced by partial occlusion of the coronary artery in dogs. 209 18

The recovery of both contractile performance and metabolic response of rat heart following 1 h of ischemia after equilibration with glucose + insulin (glucose-ischemia) or with pyruvate (pyruvate-ischemia), was tested in normoxic reperfusion in the presence of glucose + insulin, pyruvate, lactate or acetate. In glucose-ischemia only the reperfusion with pyruvate results in a complete recovery of the contractile force (left ventricular pressure, LVP) (170%) and good recovery of high energy phosphate compounds. Lower LVP and tissue energy charge were found in glucose reperfusion and even less in lactate and acetate reperfusion. Disappearance of the IMP accumulated during ischemia is evident only in the pyruvate reperfusion indicating a higher metabolic recovery. On the contrary in pyruvate-ischemia all types of reperfusion tested were effective in reactivating the contractile force (although acetate to a lesser extent); the contractile activity was accompanied by a good recovery of phosphocreatine, ATP, energy charge and by the decrease of IMP. Large decreases of adenine nucleotides and NADP and lower decreases of NAD are observed during ischemia/reperfusion in both systems. Pyruvate-ischemia is quite similar to, if not worse than glucose-ischemia, for all the metabolic parameters considered, but not worse for the possibility of recovery. Some specific effect of pyruvate should be exerted during the ischemic phase. The mechanism of pyruvate protection is discussed in relationship to: (i) the possible activation of pyruvate dehydrogenase, (ii) the activation of NADPH-dependent peroxide scavenging systems, (iii) the direct scavenging action of pyruvate on H2O2.
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PMID:The protective action of pyruvate on recovery of ischemic rat heart: comparison with other oxidizable substrates. 218 87

We have previously shown that high concentrations of fatty acids depress reperfusion recovery of ischemic rat hearts as a result of a fatty acid inhibition of glucose oxidation. In this study, we determined whether dichloroacetate, an activator of pyruvate dehydrogenase, could overcome fatty acid inhibition of glucose oxidation and thereby improve mechanical recovery of hearts reperfused after a period of transient global ischemia. Isolated working rat hearts, perfused with 11 mM glucose, 1.2 mM palmitate, and 500 microU/ml insulin, were subjected to a 30-min period of no flow ischemia, followed by a 30-min period of reperfusion. Under these conditions, control hearts recovered 37% of preischemic function. The addition of 1 mM dichloroacetate to the perfusate at reperfusion resulted in a significant improvement in recovery of mechanical function (to 73% of preischemic function). When dichloroacetate was added before the onset of ischemia, however, this protective effect was lost, and a significant increase in myocardial lactate accumulation during ischemia was observed. The effects of dichloroacetate on glucose oxidation rates in both nonischemic and reperfused ischemic hearts was determined by perfusing hearts with 11 mM [U-14C]glucose and 1.2 mM palmitate and quantitatively collecting 14CO2 produced by the heart. In nonischemic hearts, 1 mM dichloroacetate increased steady-state glucose oxidation rates from 298 +/- 69 to 1,223 +/- 135 nmol.g dry wt-1.min-1. The addition of dichloroacetate to hearts reperfused after a 25-min period of ischemia also increased glucose oxidation rates from (112 +/- 25 to 561 +/- 83 nmol.g dry wt-1.min-1).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dichloroacetate stimulation of glucose oxidation improves recovery of ischemic rat hearts. 222 Nov 15

Mitochondrial pyruvate-supported respiration was studied in vitro under conditions known to exist following ischemia, i.e., elevated extramitochondrial Ca2+, Na+, and peroxide. Ca2+ alone (7-10 nmol/mg) decreased state 3 and increased state 4 respiration to 81 and 141% of control values, respectively. Sodium (15 mM) and/or tert-butyl hydroperoxide (tBOOH; up to 2,000 nmol/mg protein) alone had no effect on respiration; however, Na+ or tBOOH in combination with Ca2+ dramatically altered respiration. Respiratory inhibition induced by Ca2+ and tBOOH does not involve pyruvate dehydrogenase (PDH) inhibition since PDH flux increased linearly with tBOOH concentration (R = 0.96). Calcium potentiated tBOOH-induced mitochondrial NAD(P)H oxidation and shifted the redox state of cytochrome b from 67 to 47% reduced. Calcium (5.5 nmol/mg) plus Na+ (15 mM) decreased state 3 and increased state 4 respiratory rates to 55 and 202% of control values, respectively. Sodium- as well as tBOOH-induced state 3 inhibition required mitochondrial Ca2+ uptake because ruthenium red addition before Ca2+ addition negated the effect. The increase in state 4 respiration involved Ca2+ cycling since ruthenium red immediately returned state 4 rates back to control values. The mechanisms for the observed Ca2(+)-, Na(+)-, and tBOOH-induced alterations in pyruvate-supported respiration in vitro are discussed and a multifactorial etiology for mitochondrial respiratory dysfunction following cerebral ischemia in vivo is proposed.
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PMID:Effect of peroxide, sodium, and calcium on brain mitochondrial respiration in vitro: potential role in cerebral ischemia and reperfusion. 231 94

Transient cerebral ischemia in normoglycemic animals is followed by a decrease in glucose utilization, reflecting a postischemic cerebral metabolic depression and a reduction in the activity of the pyruvate dehydrogenase complex (PDHC). Preischemic hyperglycemia, which aggravates ischemic brain damage and invariably causes seizure, is known to further reduce cerebral metabolic rate. To investigate whether these effects are accompanied by changes in PDHC activity, the postischemic cerebral cortical activity of this enzyme was investigated in rats with preischemic hyperglycemia (plasma glucose 20-25 mM). The results were compared with those obtained in normoglycemic animals (plasma glucose 5-10 mM). The activated portion of PDHC and total PDHC activity were measured in neocortical samples as the rate of decarboxylation of [14C]pyruvate in crude brain mitochondrial homogenates after 5 min, 15 min, 1 h, 6 h, and 18 h of recirculation following 15 min of incomplete cerebral ischemia. In normoglycemic animals the fraction of activated PDHC, which rises abruptly during ischemia, was reduced to 19-25% during recirculation compared with 30% in sham-operated controls. In hyperglycemic rats the fraction of activated PDHC was higher during the first 15 min of recirculation. However, after 1 and 6 h of recirculation, the fraction was reduced to values similar to those measured in normoglycemic animals. Fifteen of 26 rats experienced early (1-4 h post ischemia) seizures in the recovery period. The PDHC activity appeared unchanged prior to these early postischemic seizures. We conclude that the accentuated depression of postischemic metabolic rate observed in hyperglycemic animals is not coupled to a corresponding postischemic depression of PDHC.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Preischemic hyperglycemia and postischemic alteration of rat brain pyruvate dehydrogenase activity. 234 83

Hyperglycemia has been shown to exacerbate neurological deficit associated with central nervous system ischemia. Iodoacetate or dichloroacetate was administered intraperitoneally to rats in a study to examine the role of glycolysis in hyperglycemic exacerbation of neurological deficit. Sprague-Dawley rats were injected with saline, iodoacetate, or dichloroacetate and then made paraplegic by temporary occlusion for 10, 12, 13, or 15 minutes of the right and left subclavian arteries and the aorta distal to the left subclavian artery. Glycolytic blockage by iodoacetate was lethal in doses of 15 mg/kg or more, whereas rats receiving 10 mg/kg survived but showed no significant neurological improvement compared to the saline-treated control group. Dichloroacetate, 500 mg/kg, protected neurological function, which suggests a possible detrimental role for lactate accumulation and the benefit of maintaining tricarboxylic acid cycle activity by stimulating pyruvate dehydrogenase. The protection seen with dichloroacetate depended on the severity of ischemic injury. Dichloroacetate administration had a minimal effect on neurological outcome with occlusion periods of 13 and 15 minutes, mild improvement with 12 minutes of occlusion, and a significant protective effect with a 10-minute occlusion period. The dose-response nature of ischemic injury and neurological outcome in this rat model of paraplegia therefore appears to play an important role in determining the effect observed with a specific intervention.
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PMID:Neurological protection by dichloroacetate depending on the severity of injury in the paraplegic rat. 235 11


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