Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the present study was 2-fold: (1) to determine the ratio between the amount of GAD67 and GAD65 (two isoforms of the GABA synthetizing enzyme glutamic acid decarboxylase) in nerve endings in the mature rat cerebral cortex damaged by hypoxia-ischemia during early postnatal life; and (2) to compare two different computer-assisted procedures developed for quantitative analysis of immunofluorescence images obtained with a confocal laser scanning microscope (CLSM). One procedure was based on a program present in the standard Leica CLSM software packet for full-field analysis, the other on a specially written program for object-oriented analysis run on a Kontron IBAS-KAT image analysis system. To this end, rat pups were unilaterally exposed to hypoxic-ischemic conditions and, after a survival period of 6.5 months, sacrificed by perfusion fixation. After dissection of the brain and vibratome sectioning, three animals with substantial damage on one cortical side were selected. Sections of these animals were double-stained with primary antibodies against GAD67 and GAD65 and fluorophore-conjugated secondary antibodies and subsequently sampled with a CLSM. Analysis of the CLSM images with both computer-assisted procedures showed for all three animals a clear tendency to higher GAD67/GAD65 ratios in cortical GABAergic nerve endings on the hypoxia-damaged side than in matched areas on the contralateral side. This outcome led to the following conclusions. (1) The correspondence between the outcome of both analysis procedures indicates that both procedures are valid for quantification of immunofluorescence images of nerve endings obtained with a CLSM. (2) The outcome lends further support to our view that hypoxic-ischemic encephalopathy, sustained during early postnatal life, may result in an unstable cortical network generating abnormal synchronizations and oscillations which can be amplified and propagated as true epileptic discharges. In such a network both excitatory and inhibitory processes are tonically enhanced, the latter probably as a homeostatic reaction tending to keep abnormal excitation within physiological limits.
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PMID:Quantitative immunofluorescence data suggest a permanently enhanced GAD67/GAD65 ratio in nerve endings in rat cerebral cortex damaged by early postnatal hypoxia-ischemia: a comparison between two computer-assisted procedures for quantification of confocal laser scanning microscopic immunofluorescence images. 782 Jun 25

Trimetazidine is a clinically effective antianginal agent that has no negative inotropic or vasodilator properties. Although it is thought to have direct cytoprotective actions on the myocardium, the mechanism(s) by which this occurs is as yet undefined. In this study, we determined what effects trimetazidine has on both fatty acid and glucose metabolism in isolated working rat hearts and on the activities of various enzymes involved in fatty acid oxidation. Hearts were perfused with Krebs-Henseleit solution containing 100 microU/mL insulin, 3% albumin, 5 mmol/L glucose, and fatty acids of different chain lengths. Both glucose and fatty acids were appropriately radiolabeled with either (3)H or (14)C for measurement of glycolysis, glucose oxidation, and fatty acid oxidation. Trimetazidine had no effect on myocardial oxygen consumption or cardiac work under any aerobic perfusion condition used. In hearts perfused with 5 mmol/L glucose and 0.4 mmol/L palmitate, trimetazidine decreased the rate of palmitate oxidation from 488+/-24 to 408+/-15 nmol x g dry weight(-1) x minute(-1) (P<0.05), whereas it increased rates of glucose oxidation from 1889+/-119 to 2378+/-166 nmol x g dry weight(-1) x minute(-1) (P<0.05). In hearts subjected to low-flow ischemia, trimetazidine resulted in a 210% increase in glucose oxidation rates. In both aerobic and ischemic hearts, glycolytic rates were unaltered by trimetazidine. The effects of trimetazidine on glucose oxidation were accompanied by a 37% increase in the active form of pyruvate dehydrogenase, the rate-limiting enzyme for glucose oxidation. No effect of trimetazidine was observed on glycolysis, glucose oxidation, fatty acid oxidation, or active pyruvate dehydrogenase when palmitate was substituted with 0.8 mmol/L octanoate or 1.6 mmol/L butyrate, suggesting that trimetazidine directly inhibits long-chain fatty acid oxidation. This reduction in fatty acid oxidation was accompanied by a significant decrease in the activity of the long-chain isoform of the last enzyme involved in fatty acid beta-oxidation, 3-ketoacyl coenzyme A (CoA) thiolase activity (IC(50) of 75 nmol/L). In contrast, concentrations of trimetazidine in excess of 10 and 100 micromol/L were needed to inhibit the medium- and short-chain forms of 3-ketoacyl CoA thiolase, respectively. Previous studies have shown that inhibition of fatty acid oxidation and stimulation of glucose oxidation can protect the ischemic heart. Therefore, our data suggest that the antianginal effects of trimetazidine may occur because of an inhibition of long-chain 3-ketoacyl CoA thiolase activity, which results in a reduction in fatty acid oxidation and a stimulation of glucose oxidation.
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PMID:The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. 1072 Apr 6

Trimetazidine acts as an effective antianginal clinical agent by modulating cardiac energy metabolism. Recent published data support the hypothesis that trimetazidine selectively inhibits long-chain 3-ketoacyl CoA thiolase (LC 3-KAT), thereby reducing fatty acid oxidation resulting in clinical benefit. The aim of this study was to assess whether trimetazidine and ranolazine, which may also act as a metabolic modulator, are specific inhibitors of LC 3-KAT. We have demonstrated that trimetazidine and ranolazine do not inhibit crude and purified rat heart or recombinant human LC 3-KAT by methods that both assess the ability of LC 3-KAT to turnover specific substrate, and LC 3-KAT activity as a functional component of intact cellular beta-oxidation. Furthermore, we have demonstrated that trimetazidine does not inhibit any component of beta-oxidation in an isolated human cardiomyocyte cell line. Ranolazine, however, did demonstrate a partial inhibition of beta-oxidation in a dose-dependent manner (12% at 100 micromol/L and 30% at 300 micromol/L). Both trimetazidine (10 micromol/L) and ranolazine (20 micromol/L) improved the recovery of cardiac function after a period of no flow ischemia in the isolated working rat heart perfused with a buffer containing a relatively high concentration (1.2 mmol/L) of free fatty acid. In summary, both trimetazidine and ranolazine were able to improve ischemic cardiac function but inhibition of LC 3-KAT is not part of their mechanism of action. The full text of this article is available online at http://www.circresaha.org.
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PMID:The antianginal agent trimetazidine does not exert its functional benefit via inhibition of mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. 1286 92

High rates of fatty acid oxidation in the heart and subsequent inhibition of glucose oxidation contributes to the severity of myocardial ischemia. These adverse effects of fatty acids can be overcome by stimulating glucose oxidation, either directly or secondary to an inhibition of fatty acid oxidation. We recently demonstrated that trimetazidine stimulates glucose oxidation in the heart secondary to inhibition of fatty acid oxidation. This inhibition of fatty acid oxidation was attributed to an inhibition of mitochondrial long-chain 3-ketoacyl CoA thiolase (LC 3-KAT), an enzyme of fatty acid beta-oxidation. However, the accompanying Research Commentary of MacInnes et al suggests that trimetazidine does not inhibit cardiac LC 3-KAT. This discrepancy with our data can be attributed to the reversible competitive nature of trimetazidine inhibition of LC 3-KAT. In the presence of 2.5 micromol/L 3-keto-hexadecanoyl CoA (KHCoA), trimetazidine resulted in a 50% inhibition of LC-3-KAT activity. However, the inhibition of LC 3-KAT could be completely reversed by increasing substrate (3-keto-hexadecanoyl CoA, KHCoA) concentrations to 15 micromol/L even at high concentrations of trimetazidine (100 micromol/L). The study of MacInnes et al was performed using concentrations of 3K-HCoA in excess of 16 micromol/L, a concentration that would completely overcome 100 micromol/L trimetazidine inhibition of LC 3-KAT. Therefore, the lack of inhibition of LC 3-KAT by trimetazidine in the MacInnes et al study can easily be explained by the high concentration of KHCoA substrate used in their experiments. In isolated working hearts perfused with high levels of fatty acids, we found that trimetazidine (100 micromol/L) significantly improves functional recovery of hearts subjected to a 30-minute period of global no-flow ischemia. This occurred in the absence of changes in oxygen consumption resulting in an improved increase in cardiac efficiency. Combined with our previous studies, we conclude that trimetazidine inhibition of LC 3-KAT decreases fatty acid oxidation and stimulates glucose oxidation, resulting in an improvement in cardiac function and efficiency after ischemia. The full text of this article is available online at http://www.circresaha.org.
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PMID:Beneficial effects of trimetazidine in ex vivo working ischemic hearts are due to a stimulation of glucose oxidation secondary to inhibition of long-chain 3-ketoacyl coenzyme a thiolase. 1286 91

The accumulated data indicate that massively released excitatory amino acids play a major role in mediating the acute ischemic neuronal degeneration. Kynurenic acid (KYNA), the endogenous glutamate receptor antagonist, displaying a particularly high affinity for the glycine-site of N-methyl-D-aspartate (NMDA) receptor, was shown to ameliorate ischemic brain damage and its altered metabolism was implicated in the pathogenesis of neurodegeneration during ischemia/anoxia. Thus, we investigated the effect of transient global ischemia in gerbils on the endogenous levels of KYNA and the activity of its biosynthethic enzymes, kynurenine aminotransferases I (KAT I) and II (KAT II) in the hippocampus, 24 and 72 h after the ischemic episode. The level of KYNA in CA1 area was not altered 24 and 72 h following transient global ischemia (39.7 +/- 3.1 vs. 44.8 +/- 4.2, and 46.3 +/- 4.0 vs. 47.8 +/- 3.9 fmol/mg of tissue). Similarly, the activities of KATs in CA1 area were not changed and reached 1.91 +/- 0.11 vs. 1.8 +/- 0.19 and 1.86 +/- 0.1 vs. 1.7 +/- 0.15 (KAT I), and 0.56 +/- 0.2 vs. 0.43 +/- 0.16 and 0.54 +/- 0.08 vs. 0.55 +/- 0.17 (KAT II) pmol KYNA/mg of tissue/h, respectively. The presented data indicate that KYNA production is preserved in CA1 area of gerbil hippocampus during early stages after ischemic insult.
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PMID:Endogenous level of kynurenic acid and activities of kynurenine aminotransferases following transient global ischemia in the gerbil hippocampus. 1450 24

Although early reperfusion of ischemic myocardium is now considered to be the only intervention able to restore the various cellular functions altered by ischemia and to prevent progression toward cell death of myocardial cells due to necrosis or apoptosis, reperfusion is accompanied by various manifestations grouped under the heading of reperfusion damage or reperfusion syndrome. Functional recovery is therefore not immediate, but usually appears after a certain delay following a period of contractile dysfunction (myocardial stunning) lasting for several hours or even days after the start of reperfusion. The cellular mechanisms underlying the reperfusion damage may involve cellular calcium overload, over-production of oxygen-derived free radicals, cellular acidosis, inflammatory reaction, and microcirculatory dysfunction. Numerous pharmacological studies have been conducted to limit such reperfusion injury and, consequently, prevent stunning and/or reperfusion-induced arrhythmias. A number of experimental and clinical studies have demonstrated the beneficial effects of trimetazidine, a drug that inhibits the long-chain mitochondrial 3-ketoacyl coenzyme A thiolase enzyme in the myocyte, resulting in a shift from fatty acid oxidation to glucose oxidation. This optimization of cardiac metabolism results in direct anti-ischemic effects, limiting calcium accumulation and acidosis, inflammation and oxygen free radical production, and improvement of coronary microcirculation following reperfusion. This agent appears to be particularly promising clinically in the treatment of reperfusion injury, for example in combination with reperfusion strategies during the acute phase of myocardial ischemia or infarction, or in the reduction of the pro-remodeling effects of ischemia in patients with chronic ischemic syndrome and left ventricular dysfunction.
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PMID:[Trimetazidine and cardioprotection during ischemia-reperfusion]. 1507 75

Despite increasing pharmacological and mechanical treatment options, ischemic heart disease continues to be associated with considerable patient mortality and morbidity. The estimates of the direct and indirect costs associated with chronic stable angina amount to billions of dollars. Given the epidemiological and economic magnitude of the problem, the need for more effective therapies is self-evident. Based on current guidelines, the management of ischemic heart disease has progressively broadened to include risk factor modification, patient education, and pharmacological therapy. The latter includes i) classic antianginal agents such as beta-blockers, calcium antagonists, and nitrates, and ii) drugs for secondary prevention, such as aspirin, clopidogrel, statins, and angiotensin-converting enzyme inhibitors. Tailoring therapy to individual needs has become even more challenging because of the marked changes in the clinical profile of patients with chronic ischemic heart disease. Compared with the past, today's patients tend to be older, to have undergone revascularization procedures, and to frequently have associated illnesses, including heart failure and diabetes. Significant progress has been made in recent years in understanding the role of cardiac energy metabolism in the pathogenesis of myocardial ischemia. A better understanding of metabolic derangements associated with ischemia and reperfusion is translating into innovative therapeutic approaches. Optimization of cardiac energy metabolism is based on promoting cardiac glucose oxidation. This has been proved to enhance cardiac function and protect myocardial tissue against ischemia-reperfusion injury. A new class of metabolic agents, known as the 3-ketoacyl coenzyme A thiolase inhibitors (trimetazidine), is able to elicit an increase in glucose and lactate combustion secondary to partial inhibition of fatty acid oxidation, producing clinical benefits in patients with ischemic heart disease.
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PMID:["Persistent" angina: rationale for a metabolic approach]. 1507 76

The fraction of glucose passing through glycolysis that is oxidized is low in hypertrophied hearts, a pattern of glucose use associated with poor postischemic contractile function. We tested the hypothesis that trimetazidine, a partial 3-ketoacyl coenzyme A thiolase inhibitor, would stimulate glucose oxidation and, thereby, improve fractional glucose oxidation and postischemic function of hypertrophied hearts. Function, glycolysis, and oxidation of glucose, lactate, and palmitate were measured before and after global no-flow ischemia in isolated working hearts from sham-operated (control) and aortic-constricted (hypertrophied) male Sprague-Dawley rats in the presence or absence of 1 microM trimetazidine. Heart function was significantly improved by trimetazidine after ischemia, but only in hypertrophied hearts, with function improving to values in untreated control hearts. This effect occurred in association with relatively minor changes in oxidative metabolism. However, trimetazidine reduced glycolysis by approximately 30% but did so only in hypertrophied hearts, an unexpected novel action of this agent that resulted in a larger fractional oxidation of glucose, effectively normalizing it in hypertrophied hearts. Thus, trimetazidine normalizes postischemic function and fractional glucose oxidation in hypertrophied hearts, mainly by reducing glycolysis. These data extend the potential usefulness of trimetazidine and provide support for its use as a means to improve postischemic function of pressure overload hypertrophied hearts.
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PMID:Trimetazidine normalizes postischemic function of hypertrophied rat hearts. 1584 Jul 66

The pivotal therapeutic role of myocardial metabolic modulation in ischemic heart disease (IHD) is increasingly recognized. Among the others, inhibitors of free fatty acids (FFA) oxidation have been consistently shown to play an important role in the therapeutic strategy of IHD patients. Additionally, abnormalities of glucose homeostasis are consistently present in patients with IHD, definitely contributing to the progression of the primary disease. If not adequately treated, in most patients glucose metabolism abnormalities will heavily contribute to the occurrence of complications, of whom severe left ventricular dysfunction is at present one of the most frequent and insidious. Apart from a meticulous metabolic control of frank diabetes, special attention should be also paid to insulin resistance, a condition that is generally underdiagnosed as a distinct clinical entity. An important metabolic alteration in diabetic patients is the increase in free fatty acid concentrations and the increased muscular and myocardial free fatty acid uptake and oxidation. The increased uptake and utilization of free fatty acid and the reduced utilization of glucose as source of energy during stress and ischemia are responsible for the increased susceptibility of the diabetic heart to myocardial ischemia and to a greater decrease of myocardial performance for a given amount of ischemia compared to non diabetic hearts. In order to shift cardiac metabolism from FFA to preferential glucose utilization, the use of FFA inhibitors has been advocated. Among FFA inhibitors etomoxir, perhexiline, oxfenicine and trimetazidine have been evaluated. Among them, trimetazidine, specifically a 3-ketoacyl coenzyme A thiolase inhibitor, has been shown to improve overall glucose metabolism in IHD patients with diabetes and left ventricular dysfunction. The observed combined beneficial effects of FFA inhibitors on myocardial ischemia, left ventricular function and glucose metabolism, represent an additional advantage of these drugs, especially when myocardial and glucose metabolism abnormalities coexist. In this paper, the recent literature on the beneficial therapeutic effects of FFA oxidation inhibitors on myocardial ischemia, left ventricular dysfunction and glucose metabolism in patients with ischemic heart disease and abnormalities of carbohydrate metabolism is reviewed and discussed.
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PMID:Effects of metabolic approach in diabetic patients with coronary artery disease. 1927 50

Diabetic cardiomyopathy is a type of cardiac dysfunction resulting from diabetes, independent of vascular or valvular pathology. It clinically manifests initially as asymptomatic diastolic dysfunction and then progresses to symptomatic heart failure. Two major contributors to the development of diabetic cardiomyopathy, which are unique to diabetes, are hyperglycemia and diabetes-related alterations in myocardial metabolism. Diabetes mellitus is characterized by reduced glucose and lactate metabolism and enhanced fatty acid metabolism, which are the early consequences of the disease. Studies on the effect of intensive glucose control on heart failure events in patients with diabetes have been conducted with neutral results. However, no study on the effect of metabolic modulators on the prevention of heart failure has been reported. Trimetazidine, a 3-ketoacyl coenzyme A thiolase (3-KAT) inhibitor, shifts cardiac energy metabolism from free fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-KAT, and is used clinically as an effective antianginal agent. Studies have shown that trimetazidine improves heart function in patients with idiopathic cardiomyopathy and in diabetic patients with cardiac ischemia or heart failure. In addition to being effective, trimetazidine has only mild side effects. Therefore, instead of routine administration of trimetazidine for the treatment of diabetic cardiomyopathy, we hypothesize that the early application of trimetazidine may prevent or ameliorate diabetic cardiomyopathy. In addition to life style modifications, ACEI, ARB, and beta-blockers, which have been recommended in the past, trimetazidine should be administered to those patients with impaired glucose tolerance or patients in the early course of diabetes. In this way, we may reduce the prevalence of heart failure and improve the long-term survival of patients with diabetes through early normalization of the myocardial substrate metabolism.
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PMID:Early administration of trimetazidine may prevent or ameliorate diabetic cardiomyopathy. 2093 48


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