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 relationship between tissue levels of fatty acid metabolites in ischemic and reperfused hearts and recovery of mechanical function of these hearts on reperfusion was studied. Isolated rat hearts were exposed to global ischemia for periods up to 60 min under various conditions of coronary flow, O2 supply, and fatty acid concentrations and were then reperfused for either 15 or 30 min under aerobic conditions both with and without fatty acids present. Tissue levels of ATP, creatine phosphate, long-chain acyl CoA, and long-chain acyl carnitine were determined at the end of the ischemic and reperfusion periods. In some experiments K+ arrest during ischemia was used to prevent adenine nucleotide depletion both in the absence and presence of high fatty acids. Although the ability of these hearts to recover their preischemic mechanical function varied from 8 to 90% and tissue levels of acyl CoA and acyl carnitine during ischemia varied from 3- to 10-fold depending on the condition, no correlation was found between the recovery of function during reperfusion and either the presence of fatty acid or high levels of tissue long-chain acyl CoA and carnitine esters during ischemia.
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PMID:Recovery of ventricular function in reperfused ischemic rat hearts exposed to fatty acids. 403 99

Myocardial mitochondria (MCh), isolated with rotenone (MCh + RO) and in absence of rotenone (MCh - RO), were studied in rabbits with ischemia (0.5 hr autolysis) and in controls. Content of acyl-CoA was increased by 50%, linoleic acid - by 49% and lysophosphatidyl choline - by 37% in MCh + RO of control animals as compared with the MCh - RO preparation. In the MCh + RO preparation from rabbits with ischemia content of acyl-CoA was increased by 62%, while concentration of free fatty acids (FFA) and phospholipids was similar to those of the MCh - RO preparation. After isolation of mitochondria with rotenone composition of adenine nucleotides was distinctly altered. Content of ATP was decreased by 27% in mitochondria of both ischemic and control animals, although total amount of adenine nucleotides was decreased only slightly. As shown by estimation of succinate oxidation and membrane potential rotenone did not affect the mitochondrial respiration. In mitochondria of ischemic rabbits concentrations of FFA and lysophosphatidyl choline were increased, whereas content of ATP, total amount of adenine nucleotides, the rate of succinate oxidation and membrane potential were decreased. The method developed, isolation of mitochondria with rotenone, may be used in studies of the role of acyl-CoA in energy metabolism of cells.
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PMID:[Effect of ischemia and rotenone on lipid and adenine nucleotide levels and functional activity of heart mitochondria]. 409 Mar 66

We investigated the protective effects of beta-adrenergic blocking agents on ischemia-induced mitochondrial dysfunction in 42 anesthetized mongrel dogs. The animals, divided into 6 groups of 7 dogs each, were premedicated with either saline for the controls, or D, L-propranolol (0.5 mg/kg), D-propranolol (0.5 mg/kg), D, L-acebutolol (2.5 mg/kg), D, L-pindolol (0.1 mg/kg), or L-isoproterenol (0.2 microgram/kg/min, for 10 min). Myocardial mitochondria were prepared from both the normal and the ischemic areas after 30 min of coronary ligation. The concentration of long-chain acyl-CoA was measured enzymatically. Respiratory control index, ADP/O, and the rate of oxygen consumption in State III of mitochondria were also measured. In the control group, acyl-CoA in ischemic mitochondria increased significantly compared with that in normal mitochondria, and mitochondrial dysfunction was observed. Administration of L-isoproterenol further increased acyl-CoA level and accelerated the dysfunction, whereas premedication with beta-blocking agents reduced the elevation of acyl-CoA level and prevented the dysfunction. Premedication with D-propranolol had no effect on mitochondria. Since the accumulation of acyl-CoA interferes with normal mitochondrial function, these results suggest that the protective effects of beta-blocking agents are based, at least in part, on the prevention of the accumulation of acyl-CoA esters.
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PMID:The effects of beta-blocking agents on mitochondrial function in ischemic myocardium. 614 3

The most important biochemical derangements in ischemic myocardium are the decrease of energy rich phosphates (ATP and phosphocreatine) and intracellular acidosis, both of which contribute to a rapid loss of the contractile function. How and to which extent the alterations of carbohydrate and lipid metabolism are involved in these derangements is briefly discussed. In conditions of oxygen restriction the synchronism between the cytosolic and mitochondrial phase of carbohydrate metabolism is disrupted and beta-oxidation of long chain fatty acids is prevented. Consequently less ATP and more lactate is produced and fatty acids accumulate together with their activation products, acyl CoA in particular. In ischemia free carnitine is also decreased and the carnitine dependent functions (acyl transfer across mitochondrial membrane and pyruvate and alpha ketoglutarate dehydrogenase stimulation) impaired. The meaning of the altered carnitine dependent functions is considered together with the possible (demonstrated and supposed) metabolic effects of carnitine administration in cardiac ischemia.
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PMID:Biochemical derangements in ischemic myocardium: the role of carnitine. 624 Apr 23

Tissue contents of intermediates of fatty acid metabolism were determined in isolated volume-overloaded rat hearts, 3 months after creation of an aorto-caval fistula. In the absence of any modification of blood carnitine, tissue levels of total carnitine were reduced by 33% in overloaded hearts compared to normal hearts. Total tissue CoA was unchanged. Fifteen minutes of whole-heart ischemia (i.e. a 50% reduction in coronary flow) did not increase levels of long-chain acyl esters of CoA and carnitine of the overloaded myocardium, in the presence of glucose as the only exogenous substrate. This was associated with lower than normal levels of long-chain acyl carnitine under normoxic conditions. The addition of exogenous palmitate (1.5 mM) resulted in an ischemia-induced accumulation of long-chain acyl-CoA and acyl carnitine in the overloaded heart although to a smaller extent than in the normal heart under similar perfusion conditions.
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PMID:Lipid intermediates in chronically volume-overloaded rat hearts. Effect of diffuse ischemia. 624 Jun 33

At subsaturating concentrations of palmitoyl-CoA, the carnitine-dependent oxidation of the palmitoyl portion by uncoupled rat heart mitochondria was stimulated by ADP or ATP. This effect was traced to the prevention of acyl-CoA binding to adenine nucleotide translocase and the consequent sparing of acyl-CoA for acylcarnitine formation. Palmitoyl-CoA oxidation was stimulated by ITP also although ITP served neither as a transportable substrate nor as an inhibitor of ADP transport. ITP and other nontransportable nucleoside di(tri)phosphates prevented octanoyl-CoA binding to mitochondria. ITP was bound to mitochondria, and this binding was reversed by ADP, octanoyl-CoA, and carboxyatractyloside. Thus, besides a substrate site, there is a site on the translocase that binds nucleoside di(tri)phosphates, CoA and its esters, and atractylosides; inhibition of the translocase results, however, only from the binding of CoA esters of fatty acids and of atractylosides. We suggest that in O2-deficient hearts, when nucleotides decline and fatty acyl-CoA rises, the binding of the latter to the translocase becomes operational to slow fatty acylcarnitine production. By retarding the rise in amphipathic burden, this mechanism could protect heart against irreversible damage during brief periods of ischemia or hypoxia.
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PMID:Protective role of adenine nucleotide translocase in O2-deficient hearts. 633 Dec 5

Long-chain free fatty acids which, in well-oxygenated hearts are the preferred metabolic fuel, are detrimental to cardiac function under ischemic conditions. A number of metabolic products accumulate in the cell during ischemia, among which are the long-chain acyl esters of CoA and carnitine. The presence of exogenous fatty acids during ischemic perfusion results in higher tissue levels of acyl carnitine. Diabetic hearts also have higher tissue levels of long-chain acyl-CoA and acyl carnitine. Moreover the increase of these long-chain acyl esters during ischemia is greater than in the normal hearts. The rise in long-chain acyl carnitine levels in the ischemic tissue correlates with the appearance of amorphous densities in the mitochondria and with structural alteration of the inner mitochondrial membrane. Accumulation of intermediates of fatty acid metabolism likely to contribute to cellular damage during ischemia.
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PMID:[Metabolism of long chain fatty acids in the normal and pathologic heart: effects of ischemia]. 639 67

Fatty acids in excess impair mechanical function and electrical stability in ischemic hearts. The purpose of the present studies was to test whether oxfenicine, an agent capable of reducing fatty acid metabolism, can prevent these consequences and in so doing improve hemodynamic performance. Two groups of working swine hearts (n = 15), extracorporeally perfused with whole blood, were compared over 90 min of controlled coronary perfusion. An emulsion of triacylglycerols (Intralipid) with heparin were administered systemically to augment serum fatty acids threefold (0.30 to 0.92 mumol/ml). Labeled [U14C]palmitate was administered selectively into the left anterior descending coronary circulation to follow fatty acid oxidation. Coronary flow in this bed was decreased by 50% over the final 30 min of perfusion. Saline (n = 7) or oxfenicine (17-33 mg/kg, n = 8) was administered to placebo or treated animals at 30 min perfusion. 14CO2 production from labeled palmitate was decreased by 55% (P less than 0.025) at normal flows in oxfenicine-treated hearts and was reduced further during ischemia. Tissue levels of acyl carnitine were significantly reduced and acetyl CoA levels significantly increased in oxfenicine-treated hearts both in aerobic and ischemic myocardium. These changes were associated with an improvement in mechanical function. Left ventricular systolic and developed pressures and maximum left ventricular dP/dt were increased by 36 delta %, P less than 0.01; 46 delta %, P less than 0.025; and 41 delta %, P less than 0.025, respectively, at end ischemia as compared with placebo hearts.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of reducing fatty acid metabolism on mechanical function in regionally ischemic hearts. 647 33

A computer model of the fatty acid oxidation pathway in perfused rat heart was constructed. It includes uptake, activation, and beta-oxidation of fatty acids, triglyceride synthesis and hydrolysis, and carnitine-dependent transport of acyl groups across the mitochondrial membrane under pseudosteady state conditions. Fatty acid utilization may be limited by beta-oxidation in hypoxia or ischemia but probably not in aerobic conditions. Nonesterified fatty acids bound to proteins are found to be metabolically available. The model predicts that stearate, but not palmitate, can support the highest observed respiration rate for perfused rat heart without supplementation by other substrates. Fatty acids are preferentially oxidized rather than being stored as triglycerides because the cystosolic acyl CoA level is lower than the Km for triglyceride synthesis. It is suggested that feedback inhibition of triglyceride lipase regulates utilization of triglycerides as fuel in aerobic hearts.
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PMID:Computer simulation of metabolism in palmitate-perfused rat heart. I. Palmitate oxidation. 659 96

Free arachidonic acid is released rapidly in the brain at the onset of ischemia and during convulsions. The transient nature of this phenomenon indicates the existence of an active reacylation system for this fatty acid, likely an arachidonoyl-CoA synthetase-arachidonoyl transferase. The first of these enzymatic activities in brain microsomes was studied and it was found that [1-14C]arachidonic acid is rapidly activated and shows an absolute requirement for ATP and CoA. MgCl2 enhances this activity 10-fold. The optimum pH is 8.5, and the apparent Km values for the radiolabeled substrate, ATP, CoA, and MgCl2 are 36, 154, 8, and 182 microM, respectively. The apparent Vmax is 32.4 nmol/min/mg protein for arachidonic acid. The presence of Triton X-100 (0.1%) in the assay medium caused a significant reduction in apparent Km (9.4 microM) and Vmax (25.7 nmol/min/mg protein) values. The enzymatic activity is thermolabile with a T1/2 of less than 1 min at 45 degrees C and a maximal activity at 40 degrees C. The breaking point or transition temperature is 25 degrees C in an Arrhenius plot. The activation energies were 95 kJ/mol from 0 to 25 degrees C and 30 kJ/mol from 25 to 40 degrees C. Fatty acid competition studies showed inhibition by unlabeled docosahexaenoic and arachidonic acids with a Ki of 31 and 37 microM, respectively, in the absence and 18 and 7.7 microM in the presence of Triton X-100. Palmitic acid and oleic acid slightly inhibited the reaction whereas linoleic acid inhibited it to a moderate extent. It is concluded that this very active enzyme can activate arachidonic acid as well as docosahexaenoic acid in brain microsomes. In addition, this reaction may be involved in regulating the pool size of these free fatty acids in brain by rapid removal through activation, thus limiting eicosanoid formation. Moreover, the rapid formation of polyenoic acyl-coenzyme A may participate in the retention of essential fatty acids in the central nervous system.
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PMID:Kinetic properties of arachidonoyl-coenzyme A synthetase in rat brain microsomes. 663 46


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