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

Long chain free fatty acids (FFA) are the preferred metabolic substrates of myocardium under aerobic conditions. However, under ischemic conditions long chain FFA have been shown to be harmful both clinically and experimentally. Serum levels of free fatty acids frequently are elevated in patients with myocardial ischemia. The proposed mechanisms of the detrimental effects of free fatty acids include: (1) accumulation of toxic intermediates of fatty acid metabolism, such as long chain acyl-CoA thioesters and long chain acylcarnitines, (2) inhibition of glucose utilization, particularly glycolysis, during ischemia and/or reperfusion, and (3) uncoupling of oxidative metabolism from electron transfer. The relative importance of these mechanisms remains controversial. The primary site of FFA-induced injury appears to be the sarcolemmal and intracellular membranes and their associated enzymes. Inhibitors of free fatty acid metabolism have been shown experimentally to decrease the size of myocardial infarction and lessen postischemic cardiac dysfunction in animal models of regional and global ischemia. The mechanism by which FFA inhibitors improve cardiac function in the postischemic heart is controversial. Whether the effects are dependent on decreased levels of long chain intermediates and/or enhancement of glucose utilization is under investigation. Manipulation of myocardial fatty acid metabolism may prove beneficial in the treatment of myocardial ischemia, particularly during situations of controlled ischemia and reperfusion, such as percutaneous transluminal coronary angioplasty and coronary artery bypass grafting.
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PMID:Free fatty acid metabolism during myocardial ischemia and reperfusion. 904 24

To ascertain effects of total ischemia on brain phospholipid metabolism, anesthetized rats were decapitated and unesterified fatty acids and long chain acyl-CoA concentrations were analyzed in brain after 3 or 15 min. Control brain was taken from rats that were microwaved. Fatty acids were quantitated by extraction, thin layer chromatography and gas chromatography. Long-chain acyl-CoAs were quantitated by solubilization, solid phase extraction with an oligonucleotide purification cartridge and HPLC. Unesterified fatty acid concentrations increased significantly after decapitation, most dramatically for arachidonic acid (76 fold at 15 min) followed by docosahexaenoic acid. Of the acyl-CoA molecular species only the concentration of arachidonoyl-CoA was increased at 3 min and 15 min after decapitation, by 3-4 fold compared with microwaved brain. The concentration of docosahexaenoyl-CoA fell whereas concentrations of the other acyl-CoAs were unchanged. The increase in arachidonoyl-CoA after decapitation indicates that reincorporation of arachidonic acid into membrane phospholipids is possible during ischemia, likely at the expense of docosahexaenoic acid.
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PMID:Relation between free fatty acid and acyl-CoA concentrations in rat brain following decapitation. 923 26

There is evidence that dietary polyunsaturated fatty acids (PUFA) may protect against cardiovascular diseases, but the involvement of the cardiac muscle cell in this beneficial action remain largely unknown. The present study compared the respective influence of n-3 and n-6 PUFA on the function of cultured neonatal rat cardiomyocytes (CM). Cells were grown for 4 days in media enriched either n-3 (eicosapentaenoic acid, EPA and docosahexaenoic acid, DHA) or n-6 (arachidonic acid, AA) PUFA. The PUFA n-6/n-3 ratio in the phospholipids was close to 1 and 20 in the n-3 and n-6 cells, respectively. The transmembrane potentials were recorded using microelectrodes and the contractions were monitored with a photoelectric device. In physiological conditions, the increase of n-6 PUFA level in the phospholipids resulted in a significant decrease in the maximal rate of initial depolarization (-16%). In opposition, the action potential amplitude and duration were not altered, and the cell contraction outline was not affected. Ischemia was simulated in vitro using a substrate-free, hypoxia-reoxygenation procedure in a specially designed gas-flow chamber. The progressive loss of electrical activity induced by the substrate-free, hypoxic treatment was affected by the n-6/n-3 ratio, since the n-6 rich CM displayed a slower depression of the AP amplitude and duration parameters. Conversely, the recovery of the resting potential (MDP) during reoxygenation was faster in n-3 CM, whereas the recovery of the contraction parameters was unaffected by the fatty acid composition of the cells. These results suggested that, in physiological conditions, the modification of long chain PUFA balance in the phospholipids of cardiac muscle cells may modulate the initial AP upstroke, which is governed by sodium channels. Moreover, the presence of n-3 PUFA appeared to accelerate the electrical depression during substrate-free hypoxia but in turn to allow a faster recovery upon reoxygenation.
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PMID:Influence of phospholipid long chain polyunsaturated fatty acid composition on neonatal rat cardiomyocyte function in physiological conditions and during glucose-free hypoxia-reoxygenation. 935 58

The purpose of the present investigation was to determine whether the beneficial effects of polyunsaturated fatty acids (PUFA) may influence ischemia-reperfusion-induced alterations of myocardial alpha- and beta-adrenoceptor (alpha-AR, beta-AR) responsiveness. This study was carried out using monolayer cultures of neonatal rat ventricular myocytes in a substrate-free, hypoxia-reoxygenation model of ischemia. The cardiomyocytes (CM) were incubated during 4 days in media enriched either with n-6 PUFA (arachidonic acid, AA) or with n-3 PUFA (eicosapentaenoic acid, EPA, and docosahexaenoic acid, DHA). The n-6/n-3 ratio in n-3 CM was close to 1.2, compared to 20.1 in n-6 CM. The contractile parameters of n-6 CM and n-3 CM were similar in basal conditions as well as during hypoxia and reoxygenation. In basal conditions, the phospholipid (PL) enrichment with long chain n-3 PUFA resulted in an increased chronotropic response to isoproterenol (ISO) and to phenylephrine (PHE). After posthypoxic reoxygenation, the chronotropic response to beta-AR activation in n-6 CM was significantly enhanced as compared with the control response in normoxia. In opposition, the ISO-induced rise in frequency in n-3 CM in control normoxia and after reoxygenation was similar. In these n-3 CM, the changes in contractile parameters, which accompanied the chronotropic response, were also similar in reoxygenation and in normoxic periods, although the rise in shortening velocity was slightly increased after reoxygenation. In response to PHE addition, only the chronotropic effect of n-6 CM appeared significantly enhanced after hypoxic treatment. These results suggested that increasing n-3 PUFA in PL reduced the increase in alpha- and beta-AR functional responses observed after hypoxia-reoxygenation. This effect may partly account for the assumed cardiac protective effect of n-3 PUFA, through the attenuation of the functional response to catecholamines in the ischemic myocardium.
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PMID:Cross-influence of membrane polyunsaturated fatty acids and hypoxia-reoxygenation on alpha- and beta-adrenergic function of rat cardiomyocytes. 1038 Jan 17

A study has been carried out on the interaction of arachidonic acid and other long chain free fatty acids with bovine heart mitochondria. It is shown that arachidonic acid causes an uncoupling effect under state 4 respiration of intact mitochondria as well as a marked inhibition of uncoupled respiration. While, under our conditions, the uncoupling effect is independent of the fatty acid species considered, the inhibition is stronger for unsaturated acids. Experiments carried out with mitochondrial particles indicated that the arachidonic acid dependent decrease of the respiratory activity is caused by a selective inhibition of Complex I and III. It is also shown that arachidonic acid causes a remarkable increase of hydrogen peroxide production when added to mitochondria respiring with either pyruvate+malate or succinate as substrate. The production of reactive oxygen species (ROS) at the coupling site II was almost double than that at site I. The results obtained are discussed with regard to the impairment of the mitochondrial respiratory activity as occurring during the heart ischemia/reperfusion process.
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PMID:Arachidonic acid interaction with the mitochondrial electron transport chain promotes reactive oxygen species generation. 1044 19

In response to a prolonged pressure- or volume-overload, alterations occur in myocardial fatty acid, glucose, and glycogen metabolism. Oxidation of long chain fatty acids has been found to be reduced in hypertrophied hearts compared to non-hypertrophied hearts. However, this observation depends upon the degree of cardiac hypertrophy, the severity of carnitine deficiency, the concentration of fatty acid in blood or perfusate, and the myocardial workload. Glycolysis of exogenous glucose is accelerated in hypertrophied hearts. Despite the acceleration of glycolysis, glucose oxidation is not correspondingly increased leading to lower coupling between glycolysis and glucose oxidation and greater H(+) production than in non-hypertrophied hearts. Although glycogen metabolism does not differ in the absence of ischemia, synthesis and degradation of glycogen are accelerated in severely ischemic hypertrophied hearts. These alterations in carbohydrate metabolism may contribute to the increased susceptibility of hypertrophied hearts to injury during ischemia and reperfusion by causing disturbances in ion homeostasis that reduce contractile function and efficiency to a greater extent than normal. As in non-hypertrophied hearts, pharmacologic enhancement of coupling between glycolysis and glucose oxidation (e.g., by directly stimulating glucose oxidation) improves recovery of function of hypertrophied hearts after ischemia. This observation provides strong support for the concept that modulation of energy metabolism in the hypertrophied heart is a useful approach to improve function of the hypertrophied heart during ischemia and reperfusion. Future investigations are necessary to determine if alternative approaches, such as glucose-insulin-potassium infusion and inhibitors of fatty acid oxidation (e.g., ranolazine, trimetazidine), also produce beneficial effects in ischemic and reperfused hypertrophied hearts.
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PMID:Energy metabolism in the hypertrophied heart. 1198 40

D-003 is a natural mixture of long chain aliphatic acids isolated and purified from sugar cane wax. It possesses antiplatelet and antithrombotic effects as well as decreases plasma and serum levels of thromboxane B(2) (TxB(2)), meanwhile significantly and markedly raises prostacyclin (PgI(2)) levels in rats. This study was undertaken to investigate the effects of D-003 on spinal cord injury in rabbits. New Zealand rabbits were treated during 10 days with D-003 (25 and 200 mg kg(-1)) and ASA (2 mg kg(-1)) before spinal cord ischemia. Animals were subjected to 20 min of aortic occlusion and 24h of reperfusion. Clinical symptoms and histopathological changes of spinal cord were observed. The PgI(2) levels in thoracic aorta were quantified by bioassay. D-003 (25 and 200 mg kg(-1)) significantly increased the mean scores reached 4h after reperfusion, although no dose relation was observed. Twenty-four hours after reperfusion, no deaths occurred in both sham and D-003 treated groups, meanwhile in positive controls and ASA the mortality rate was 38.5% and 7.69% respectively. In addition, 100% of sham, 69% and 77% of rabbits treated with D-003 at 25 and 200 mg kg(-1), respectively, did not show histopathological changes. By the contrary, 100% of positive control animals showed severe damage and ASA-treated rabbits showed only a partial protection. Animals treated with both doses of D-003 showed PgI(2) levels significantly larger than those of positive and negative controls, an effect dose-related, while ASA 2 mg kg(-1) did not change PgI(2) values. The increase of PgI(2) levels achieved in the D-003 treated animals could be an important mechanism in the protection against the spinal cord ischemia.
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PMID:Protective effect of D-003 on experimental spinal cord ischemia in rabbits. 1464 73

Ischemic preconditioning (IP) triggers cardioprotection via a signaling pathway that converges on mitochondria. The effects of the inhibition of carnitine palmitoyltransferase I (CPT-I), a key enzyme for transport of long chain fatty acids (LCFA) into the mitochondria, on ischemia/reperfusion (I/R) injury are unknown. Here we investigated, in isolated perfused rat hearts, whether sub-chronic CPT-I inhibition (5 days i.p. injection of 25 mg/kg/day of Etomoxir) affects I/R-induced damages and whether cardioprotection by IP can be induced after this inhibition. Effects of global ischemia (30 min) and reperfusion (120 min) were examined in hearts harvested from Control (untreated), Vehicle- or Etomoxir-treated animals. In subsets of hearts from the three treated groups, IP was induced by three cycles of 3 min ischemia followed by 10 min reperfusion prior to I/R. The extent of I/R injury under each condition was assessed by changes in infarct size as well as in myocardial contractility. Postischemic contractility, as indexed by developed pressure and dP/dt(max), was similarly affected by I/R, and was similarly improved with IP in Control, Vehicle or Etomoxir treated animals. Infarct size was also similar in the three subsets without IP, and was significantly reduced by IP regardless of CPT-I inhibition. We conclude that CPT-I inhibition does not affect I/R damages. Our data also show that IP affords myocardial protection in CPT-I inhibited hearts to a degree similar to untreated animals, suggesting that a long-term treatment with the metabolic anti-ischemic agent Etomoxir does not impede the possibility to afford cardioprotection by ischemic preconditioning.
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PMID:Myocardial protection from ischemic preconditioning is not blocked by sub-chronic inhibition of carnitine palmitoyltransferase I. 1591 95

Remodeling of myocardial cell membranes is a major feature of advanced age. Mitochondrial function, crucial to sustaining energy production and management of myocardial metabolism, is impacted by age-dependent remodeling and ultimately exhibits a diminished threshold for excess Ca(2+) buffering during events that stimulate increased myocardial Ca(2+), such as augmented cardiac work, oxidative stress or post-ischemic reflow. Relative Ca(2+) intolerance, augmented superoxide formation and reduced efficiency in the management of reactive oxygen species, are important mitochondrial factors (of many) that are apparent in senescence and predispose the myocardium to be more vulnerable to ischemic injury. In addition to cell death, surviving myocytes increase in size and exhibit altered gene expression of key effector proteins, including those that sustain Ca(2+) homeostasis. Age-associated mitochondrial membrane changes include increases in membrane rigidity, cholesterol, phosphatidylcholine, omega-6 polyunsaturated fatty acids (PUFA), 4-hydroxy-2-nonenal, and decreases in omega-3 PUFA and cardiolipin. These effects have been shown in animal studies to be exaggerated by diet rich in long chain omega-6 PUFA (i.e., arachidonic acid), and have profound consequences on the efficacy of membrane proteins involved with ion homeostasis, signal transduction, redox reactions and oxidative phosphorylation. However, some of the age-related detrimental adaptations may be beneficially modified by dietary strategy. Diet rich in omega-3 PUFA reverses the age-associated membrane omega-3:omega-6 PUFA imbalance, and dysfunctional Ca(2+) metabolism, facilitating increased efficiency of mitochondrial energy production and improved tolerance of ischemia and reperfusion.
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PMID:Effect of dietary polyunsaturated fatty acids on age-related changes in cardiac mitochondrial membranes. 1591 88

Remodeling of myocardial cell membranes is a major feature of advanced age. Mitochondrial function, crucial to sustaining energy production and management of myocardial metabolism, is impacted by age-dependent remodeling and ultimately exhibits a diminished threshold for excess Ca2+ buffering during events that stimulate increased myocardial Ca2+, such as augmented cardiac work, oxidative stress or post-ischemic reflow. Relative Ca2+, intolerance, augmented superoxide formation and reduced efficiency in the management of reactive oxygen species, are important mitochondrial factors (of many) that are apparent in senescence and predispose the myocardium to be more vulnerable to ischemic injury. In addition to cell death, surviving myocytes increase in size and exhibit altered gene expression of key effector proteins, including those that sustain Ca2+ homeostasis. Age-associated mitochondrial membrane changes include increases in membrane rigidity, cholesterol, phosphatidylcholine, omega-6 polyunsaturated fatty acids (PUFA), 4-hydroxy-2-nonenal, and decreases in omega-3 PUFA and cardiolipin. These effects have been shown in animal studies to be exaggerated by diet rich in long chain omega-6 PUFA (i.e. arachidonic acid), and have profound consequences on the efficacy of membrane proteins involved with ion homeostasis, signal transduction, redox reactions and oxidative phosphorylation. However, some of the age-related detrimental adaptations may be beneficially modified by dietary strategy. Diet rich in omega-3 PUFA reverses the age-associated membrane omega-3:omega-6 PUFA imbalance, and dysfunctional Ca2+ metabolism, facilitating increased efficiency of mitochondrial energy production and improved tolerance of ischemia and reperfusion.
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PMID:Effect of dietary polyunsaturated fatty acids on age-related changes in cardiac mitochondrial membranes. 1625 72


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