Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The translocation of adenine nucleotides across the inner mitochondrial membrane and the tissue concentration of long-chain acyl-CoA esters were studied in dog heart after experimental myocardial ischemia. Ligation of the anterior coronary artery initiated events leading to an early decrease in adenine nucleotide translocase activity. A reciprocal increase in the concentration of heart tissue long-chain acyl-CoA esters was also observed. Adjacent nonischemic tissue showed changes intermediate between that of ischemic and normal heart tissue. It is postulated that a decrease in fatty acid oxidation after myocardial ischemia would lead to an accumulation of long-chain acyl-CoA esters, which in turn would inhibit adenine nucleotide translocation. The net result would be a lowering of the energy charge of the cell, adversely affecting muscle contraction and electrical conduction.
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PMID:Acyl-CoA inhibition of adenine nucleotide translocation in ischemic myocardium. 111 32

Long chain fatty acyl-CoA esters are potent in vitro and in vivo inhibitors of adenine nucleotide translocation in heart mitochondria. Within a short time following production of myocardial ischemia, the dog heart exhibits an increased concentration of long chain acyl-CoA esters associated with a decrease in adenine nucleotide translocase activity. In contrast to liver, the tricarboxylate carrier system for citrate and phosphoenolpyruvate is rather low in heart mitochondria. Phosphoenolpyruvate-stimulated calcium egress from heart mitochondria may, therefore, result from transport of this anion on the adenine nucleotide translocase. During myocardial ischemia effective modulation of these metabolite trasnport systems are disrupted by accumulation of long chain acyl-CoA esters which leads to a decrease in the overall energy charge of the cell.
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PMID:Control of energy production in myocardial ischemia. 126 92

During acute myocardial ischemia the metabolism of free fatty acids is impaired. Since the rate of beta-oxidation is reduced, the levels of acil-CoA and long-chain acyl-carnitine increase. The activity of carnitine, which permits the transport of fatty acids into the mitochondria, is reduced both by its transformation in acyl-carnitine and by its release from the cells induced by acute ischemia. The accumulation of fatty acids induces a deterioration of hemodynamic parameters and some impulse formation and conduction disturbances. Since in experimental studies L-carnitine prevents the occurrence of hemodynamic and arrhythmic complications, clinical studies with this compound have been performed during acute ischemia in man. In patients with acute myocardial infarction high doses of L-carnitine induce: a statistically significant increase in urinary concentrations of long- and short-chain carnitine esters; a statistically significant reduction of ventricular arrhythmias during the second day after the onset of symptoms; a reduction of the necrotic area as assessed by electrocardiographic and enzymatic methods.
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PMID:[The role of metabolic therapy in myocardial infarct]. 184 95

Depletion of membrane phospholipids is known to be associated with myocardial ischemia, but its relationship to the injury involved with the reperfusion of ischemic myocardium is not known. The present study was designed to relate phospholipid degradation with reperfusion injury. The isolated in situ pig heart was subjected to 60 min of regional ischemia induced by occluding the left anterior descending (LAD) coronary artery and 60 min of global ischemia by hypothermic cardioplegic arrest followed by 60 min of reperfusion. The pigs were divided into two groups. In the treatment group, the heart was preperfused with mepacrine (0.05 mM), a known phospholipase inhibitor, for 15 min prior to LAD occlusion. In the control group, the total phospholipid content was not significantly decreased during LAD occlusion and arrest, but was reduced appreciably after reperfusion. Phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol followed a similar pattern. The lowering of these phospholipids during reperfusion was accompanied by enhancement of lysophosphatidylcholine. Mepacrine restored the normal levels of these phospholipids. During reperfusion, fatty acyl CoA synthetase, lysophospholipase, and lysophosphatidylcholine acyltransferase were depressed, whereas phospholipase A2 was enhanced. Mepacrine inhibited phospholipase A2, but had no effects on the other enzymes. Mepacrine also provided significant protection against reperfusion injury, as documented by the preservation of high-energy phosphate compounds and inhibition of the appearance of creatine kinase activity in the perfusate. These results suggest that membrane phospholipids play an important role in myocardial injury associated with ischemia and reperfusion, primarily because the deacylation-reacylation cycle of phospholipid biosynthesis becomes defective.
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PMID:Role of membrane phospholipids in myocardial injury induced by ischemia and reperfusion. 294 42

Though the efficacies of procainamide and disopyramide in treating arrhythmias are well established, their precise mechanisms of antiarrhythmic action remain unclear. Arrhythmias which occur during acute myocardial ischemia can be explained partly on a metabolic basis. The accumulation of intermediates subsequent to impaired beta-oxidation of free fatty acids has been suggested as a cause of serious arrhythmias. The purpose of this study was to investigate changes in free carnitine, long chain acyl carnitine and long chain acyl CoA concentrations in the ischemic canine heart following the administration of procainamide and disopyramide. The coronary artery was occluded for 40 min and myocardial samples were prepared from both nonischemic and ischemic areas. Procainamide and disopyramide prevented the accumulation of long chain acyl carnitine and long chain acyl CoA in the ischemic myocardium. The results showed that procainamide and disopyramide had beneficial effects on fatty acid metabolism. It was suggested that one of the antiarrhythmic mechanisms of these drugs might be the prevention of the accumulation of fatty acyl derivatives in the ischemic myocardium.
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PMID:Effects of procainamide and disopyramide on long chain acyl carnitine and long chain acyl CoA concentrations in the ischemic heart. 324 36

When glucose-insulin-potassium (GIK) is infused, glucose supplies most of the energy demands of the heart. Fatty acid becomes the major substrate during fasting, pathologically increased work loads or insulin deficiency. Myocardial purine breakdown reflects myocardial energy status and influences coronary tone. Ischemia accelerates breakdown of ATP to AMP, which is further metabolized to adenosine, which causes vasodilatation and a blunted response to catecholamines. If normal circulation is restored, ADP and AMP are rapidly converted to ATP and purine metabolism is changed from degradation to salvage and de novo synthesis of purines. Ischemia impairs mitochondrial function, causing decreased capacity to oxidize fatty acids once aerobic conditions return. Thus, reperfusion with elevated plasma free fatty acids results in acyl-CoA accumulation in the heart. In diabetic animals, phosphorylation of AMP to ATP is defective in the heart, and AMP degradation is increased. Therefore, careful regulation of the blood sugar with concomitant lowering of plasma free fatty acids in diabetics with ischemic heart disease should improve myocardial salvage by preserving and repleting myocardial ATP. Thus, along with reestablishment of coronary flow and reduction in myocardial oxygen demands, may significantly reduce the morbidity of acute ischemia in diabetics.
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PMID:Myocardial fuel and energy balance, acute ischemia and diabetes. 328 57

Carnitine, certain of its derivatives, and the amino acid metabolite, taurine, when administered independently in prior studies have been shown to improve cardiac mechanic and/or metabolism. The purpose of these studies is to test a new compound, propionylcarnitine taurine (PCT), which potentially combines these actions, in a therapeutic trial to preserve function in a setting of myocardial ischemia. In the main protocol, PCT was administered (0.71 mg/kg/min I.V.) to eight extracorporeally perfused, intact, working swine hearts over a 70 min perfusion trial and compared with seven similarly prepared placebo hearts. Left anterior descending (LAD) flows were held at aerobic levels (6.3 +/- 0.3 ml/min/g dry) for 40 min and then reduced acutely by 50% for 30 min. Serum fatty acids (FA) in both groups were augmented to 1.27 +/- 0.5 mumol/ml. Contractility (measured regionally from shortening rates of ultrasonic crystals placed in the LAD circulation); myocardial oxygen consumption (MVO2); and FA oxidation (measured from 14CO2 production rates from labeled palmitate infused into the LAD perfusate) were obtained serially throughout the perfusion trials. Regional contractility was significantly increased in PCT-treated hearts as compared with placebo hearts both during normal and ischemic flows. Treatment appeared to deplete free carnitine stores in both aerobic and ischemic myocardium but failed to modify acyl CoA levels. In seven additional animals PCT was shown to independently stimulate fatty acid oxidation (about 39 delta % increase) at aerobic flows. Lastly in nine separate animals (4 placebo; 5 treatment) prepared and studied identically to those of the main protocol, taurine alone (0.2 mg/kg/min infused IV for 70 min) was without influence in reproducing mechanical benefits. Thus, PCT favorably enhances regional contractility in conditions of myocardial ischemia, presumably by the positive inotropic effects of the propionylcarnitine constituent of the compound.
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PMID:The effects of propionylcarnitine taurine on cardiac performance in aerobic and ischemic myocardium. 336 80

Oxygen free radicals and phospholipid degradation have been implicated in the pathogenesis of ischemia and reperfusion injury. The present study examines the involvement of such mechanisms in myocardial reperfusion injury in neonatal hearts. The isolated neonatal pig hearts from two different age groups, 0 to 2 days old (newborn) and 7 to 9 days old (week-old), were subjected to 60 min of normothermic global ischemia followed by 60 min of reperfusion. Although myocardial ischemia reduced superoxide dismutase, catalase, and glutathione peroxidase activities in both age groups, superoxide dismutase and catalase activities remained significantly lower in the newborn pig heart during ischemia and reperfusion. Oxidized glutathione release from the neonatal pig hearts was at minimum levels before ischemia, but it increased 10-fold at the onset of reperfusion and was significantly higher in the newborn heart. This indicates that generation of oxygen free radicals was enhanced in the newborn compared with that in the week-old heart. The increase in phospholipase A2 activity and decrease in acyl CoA synthetase and lysophosphatidylcholine acyl transferase activities during ischemia and reperfusion were associated with comparable loss of membrane phospholipids and accumulation of lysophosphatidylcholine and free fatty acids in both age groups, except that oleic acid content was significantly higher in the newborn heart during reperfusion. Myocardial damage appears to be potentiated in the newborn heart during reperfusion, as evidenced by higher release of creatine kinase and a lower content of high-energy phosphates. These results indicate that oxygen free radicals may play a crucial role in the occurrence of reperfusion injury in immature hearts.
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PMID:The mechanism of myocardial reperfusion injury in neonates. 366 15

Enzymatic pathways involved in the metabolism of lysophosphatidylcholine were investigated in rat heart myocardial cells. Acyl CoA-dependent acyltransferase activity was localized in microsomes, and was much greater than lysophospholipase activity in either cytosolic or microsomal fractions. The cytosolic lysophospholipase was more sensitive to inhibition by palmitylcarnitine in comparison to free fatty acids. In contrast, free fatty acids (oleate and palmitate) produced a greater inhibition of the microsomal acyltransferase and lysophospholipase than did palmitylcarnitine. A reduction in the assay pH to 6.5 resulted in an increase in microsomal acyltransferase and cytosolic lysophospholipase activities, but brought about a marked reduction in the microsomal lysophospholipase activity. At pH 6.5, the percentage inhibition of the microsomal acyltransferase by palmitylcarnitine was reduced, whereas the inhibition by palmitic acid was enhanced. The inhibition of the microsomal lysophospholipase by both palmitylcarnitine and palmitic acid was reduced at pH 6.5. With respect to myocardial ischemia, the inhibition of microsomal acyltransferase by free fatty acids and the reduction in microsomal lysophospholipase activity due to acidosis may contribute to the elevation of cellular lysophosphoglycerides which are arrhythmogenic.
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PMID:Regulation of lysophosphatidylcholine-metabolizing enzymes in isolated myocardial cells from rat heart. 407 68

The accumulation of intermediates subsequent to impaired beta-oxidation of free fatty acid (FFA) has been suggested as a cause of cellular damage in ischemic myocardium. We investigated the effects of propranolol and diltiazem on carnitine metabolism in ischemic myocardium. Propranolol (0.2 mg/kg/min, i.v.) and diltiazem (0.1 mg/kg/min, i.v.) were administered for 5 min, the administration started 10 min before coronary occlusion. ECGs were continuously recorded throughout the experiment. Myocardial samples were prepared from both the non-ischemic and ischemic areas 40 min after coronary ligation. Adenosine triphosphate (ATP), free carnitine, long chain acyl carnitine and long chain acyl CoA were assayed. Propranolol reduced the decrease of ATP and the accumulation of long chain acyl CoA, induced by myocardial ischemia. Diltiazem reduced the decrease of ATP and free carnitine, and the accumulation of long chain acyl carnitine in the ischemic area. Propranolol and diltiazem significantly reduced the grade of ventricular arrhythmia. These results suggest that the protective mechanisms of propranolol and diltiazem on myocardium are based, at least in part, on their beneficial effects upon myocardial carnitine metabolism.
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PMID:Effects of propranolol and diltiazem on carnitine derivatives and acyl CoA in ischemic myocardium. 409 37


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