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

The ability of ischemic preconditioning (IP) to protect the myocardium against prolonged ischemia may derive from improved energy balance. We therefore examined myocardial energy metabolism and mitochondrial oxidative phosphorylation in isolated perfused rat hearts which were either subjected (IP group), or not subjected (control group), to preconditioning prior to 30 min sustained ischemia and 30 min reperfusion. Preconditioning was achieved with two cycles of 5 min ischemia followed by 5 min reperfusion. Recovery of myocardial function was significantly greater, and creatine kinase release was significantly lower, in the IP group. Although ATP hydrolysis during the sustained ischemia remained unchanged in both groups, greater preservation of high energy phosphate (eg. ATP and CP) was observed in the IP group after reperfusion. CP content immediately after preconditioning greatly exceeded pre-ischemic values. Lactate production during the sustained ischemia was significantly lower in the IP group, suggesting a decrease in anaerobic glycolysis and a probable attenuation of intracellular acidosis. Oligomycin-sensitive mitochondrial ATPase activity in the control group was significantly decreased both after the sustained ischemia and the reperfusion, but in the IP group it did not change after the preconditioning, sustained ischemia, or reperfusion. Although atractyloside-inhibitable adenine nucleotide translocase activity was markedly decreased during sustained ischemia in both groups, its activity was significantly higher after reperfusion in the IP group. These data suggest that (1) mitochondrial ATPase contributes only slightly to ATP depletion during sustained ischemia, (2) both the CP overshoot phenomenon and the decrease in anaerobic glycolysis can be attributable to cardioprotection during the sustained ischemia, and (3) the preservation of ATPase and adenine nucleotide translocase activities may be a possible explanation for the restoration of high energy phosphates after sustained ischemia-reperfusion injury in the preconditioned hearts of rats.
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PMID:Effect of ischemic preconditioning on mitochondrial oxidative phosphorylation and high energy phosphates in rat hearts. 872 72

The mitochondrial ATPase enzyme accounts for roughly 35-50% of the overall energy demand that leads to ATP depletion under conditions of severe myocardial ischemia. In larger mammalian hearts, this energy squandering action of the ATPase is modulated by an endogenous inhibitor protein. The present studies were undertaken to characterize the time course of inhibition of the mitochondrial ATPase in canine myocardium under conditions of severe regional ischemia in vivo. In addition, we determined if the energy sparing effects of ischemic preconditioning (PC) can be explained by persistent inhibition of the mitochondrial ATPase enzyme. The circumflex coronary artery was ligated for 1.5 min (n = 4), 5 min (n = 6), or 15 min (n = 5). In a separate group (n = 7), hearts were preconditioned by four 5-min periods of ischemia each followed by 5 min of reperfusion. Sub-mitochondrial particles were prepared from the sub-endocardial zone of the ischemic and non-ischemic regions and were assayed for oligomycin-sensitive ATPase activity. ATPase activity was reduced to about 79% at 1.5 min and to approximately 55% at 5 and 15 min of ischemia, relative to non-ischemic tissue from the same heart. The rate of HEP utilization slowed concurrently with the development of ATPase inhibition. In preconditioned myocardium, ATPase activity was not significantly different from control myocardium from the same heart. We conclude that the early inhibition of the mitochondrial ATPase activity slows the utilization of high energy phosphate and thereby serves as an important endogenous cardioprotective mechanism. Nevertheless, altered activity of the ATPase is not the explanation of the energy sparing effect of ischemic preconditioning.
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PMID:Effect of reversible ischemia on the activity of the mitochondrial ATPase: relationship to ischemic preconditioning. 874 18

Rabbit, rat, and pigeon are species representative of three cardiac muscle mitochondrial ATPase regulatory classes, a, b and c, respectively. Class a species contain a full complement of higher affinity ATPase inhibitor subunit, IF1, in their cardiac muscle mitochondria and show marked IF1-mediated mitochondrial ATPase inhibition during myocardial ischemia. Class b species contain low levels of higher affinity IF1 and show very little IF1-mediated ATPase inhibition during ischemia. Class c species contain a full complement of a lower affinity form of IF1 and show a low-to-moderate level of IF1- mediated ATPase inhibition during ischemia. In the present study we perfused hearts of a member of each regulatory class through the coronary arteries with the uncoupler, carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP), before making them ischemic. We then compared net rates of cell ATP depletion during ischemia in the FCCP-treated hearts to identically treated FCCP-free hearts. Thus, we tested the relative capacities of cardiac muscle mitochondria of the three species to avert a potentially greatly increased net rate of cell ATP depletion due to ATP hydrolysis by the fully uncoupled mitochondrial ATPase. We found that FCCP-uncoupling in situ had a relatively small effect on ATP depletion during ischemia in rabbit hearts, that it dramatically accelerated ATP depletion in ischemic rat hearts, and that it had an intermediate effect on ATP depletion in ischemic pigeon hearts. These results demonstrate for the first time the relative extents to which IF1-mediated mitochondrial ATPase inhibition can slow cell ATP depletion due to the fully uncoupled mitochondrial ATPase in these three classes of hearts. They show that, in contrast to the situation in rabbit hearts, the low level of higher affinity IF1 present in the cardiac muscle mitochondria of the rat is, under these conditions, essentially nonfunctional, while the full complement of the lower affinity form of IF1 present in the cardiac muscle mitochondria of the pigeon is partially functional in that it appeared to provide an intermediate level of protection against rapid cell ATP depletion.
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PMID:IF1 function in situ in uncoupler-challenged ischemic rabbit, rat, and pigeon hearts. 879 81

One or several brief episodes of myocardial ischemia (ischemic preconditioning; IP) rapidly induces tolerance to a later ischemic challenge. This endogenous cardioprotective effect is characterized by a slower onset of cell death. A key feature and probable proximate mechanism of IP is reduced ischemic energy demand which is evident by slower use of ATP and slower accumulation of ischemic catabolites. Several mechanisms for IP and the associated metabolic slowing have been studied: The mitochondrial ATPase is a major cause of ATP hydrolysis in ischemic myocardium but slower ATP depletion in preconditioned myocardium is not due to persistent inhibition of this ATPase. Brief episodes of ischemia in dogs induce stunning as well as IP. Stunning, however, is neither necessary nor sufficient to establish the protective effects of IP. Release of norepinephrine from adrenergic cardiac nerves causes beta adrenergic receptor-mediated stimulation of adenylate cyclase, which stimulates energy-dependent processes. However, IP in dogs that were depleted of catecholamines by pretreatment with reserpine was less effective than IP in control hearts. Thus, an antiadrenergic mechanism does not fully account for the preconditioned state. Another proposed mechanism involves earlier or more complete opening of ATP-sensitive potassium (KATP+) channels. Which of these (or other) pathways mediate the energy sparing effects of ischemic preconditioning remains unknown.
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PMID:The slowing of ischemic energy demand in preconditioned myocardium. 890 52

Preconditioning is an effective mean of protecting the heart against prolonged ischemia by pretreating it with a minor insult, and the present paper reviews various controversies in this highly active field of research. In many models, adenosine plays a role by triggering the activation of protein kinase C. It may work in conjunction with other agents, such as bradykinin, but the putative role of noradrenaline is uncertain. Regulation of the enzyme producing adenosine (i.e., 5'-nucleotidase) has been reported during preconditioning but, because its activity does not seem to be associated with infarct size, it is unlikely that the hydrolase plays a pivotal role. Controversial data have been published on the involvement of mitochondrial ATPase, which may be ascribed to the poor time resolution of the experiments described; however, we do not believe that either acidosis or tissue ATP are important factors in triggering preconditioning. The role of glycolysis in the preconditioning effect remains to be firmly established; opposite mechanisms are activated in low-flow and stop-flow protocols. Although species differences regarding preconditioning exist, they seem to be more of a quantitative than a qualitative nature. The phenomenon could be clinically relevant because evidence is accumulating that preconditioning may take place during bypass surgery and coronary angioplasty if longer balloon-occlusion times are used.
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PMID:Controversies in preconditioning. 911 Jan 21

Mitochondrial F1F0 adenosinetriphosphatase (ATPase) is responsible for the majority of ATP synthesis during normoxic conditions, but under ischemic conditions it accounts for significant ATP hydrolysis. A previous study showed that preconditioning in isolated rat hearts is mediated by inhibition of this ATPase during ischemia. We tested this hypothesis in our isolated rat heart model of preconditioning. Preconditioning was accomplished by three 5-min periods of global ischemia separated by 5 min of reperfusion. This was followed by 20 min of global ischemia and 30 min of reperfusion. Preconditioning significantly enhanced reperfusion contractile function and reduced lactate dehydrogenase release but paradoxically reduced the time to onset of contracture during global ischemia. Myocardial ATP was depleted at a faster rate during the prolonged ischemia in preconditioned than in sham-treated hearts, which is consistent with the reduced time to contracture. ATP during reperfusion was repleted more rapidly in preconditioned hearts, which is consistent with their enhanced contractile function. Preconditioning significantly reduced lactate accumulation during the prolonged ischemia. We were not able to demonstrate that mitochondrial F1F0 ATPase (measured in submitochondrial particles) was inhibited by preconditioning before or during the prolonged ischemia. The mitochondrial ATPase inhibitor oligomycin significantly conserved ATP during ischemia and increased the time to the onset of contracture, which is consistent with inhibition of the mitochondrial ATPase. Our results show that preconditioning in rat hearts can be independent of mitochondrial ATPase inhibition as well as ATP conservation.
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PMID:Preconditioning in rat hearts is independent of mitochondrial F1F0 ATPase inhibition. 945 56

A brief period of ischemia and reperfusion has been shown to protect the myocardium against subsequent sustained ischemia and reperfusion injury, which is called "preconditioning". A great number of investigators have explored the mechanisms underlying this preconditioning-induced cardioprotection. This article dealt with possible mechanisms of energy metabolism and mitochondrial activity for preconditioning-induced cardioprotection. Particularly, the contribution of energy metabolites produced during a brief period of ischemia and reperfusion injury, as well as mitochondrial function that is modified by changes in mitochondrial ATPase activity, opening of mitochondrial ATP-dependent potassium channels and production of free radicals in mitochondria, to ischemic preconditioning is discussed.
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PMID:Role of energy metabolism in the preconditioned heart--a possible contribution of mitochondria. 1053 88

Modulation of mitochondrial respiratory chain, dehydrogenase, and nucleotide-metabolizing enzyme activities is fundamental to cellular protection. Here, we demonstrate that the potassium channel opener diazoxide, within its cardioprotective concentration range, modulated the activity of flavin adenine dinucleotide-dependent succinate dehydrogenase with an IC50 of 32 microM and reduced the rate of succinate-supported generation of reactive oxygen species (ROS) in heart mitochondria. 5-Hydroxydecanoic fatty acid circumvented diazoxide-inhibited succinate dehydrogenase-driven electron flow, indicating a metabolism-dependent supply of redox equivalents to the respiratory chain. In perfused rat hearts, diazoxide diminished the generation of malondialdehyde, a marker of oxidative stress, which, however, increased on diazoxide washout. This effect of diazoxide mimicked ischemic preconditioning and was associated with reduced oxidative damage on ischemia-reperfusion. Diazoxide reduced cellular and mitochondrial ATPase activities, along with nucleotide degradation, contributing to preservation of myocardial ATP levels during ischemia. Thus, by targeting nucleotide-requiring enzymes, particularly mitochondrial succinate dehydrogenase and cellular ATPases, diazoxide reduces ROS generation and nucleotide degradation, resulting in preservation of myocardial energetics under stress.
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PMID:Targeting nucleotide-requiring enzymes: implications for diazoxide-induced cardioprotection. 1266 60

Ischemic preconditioning (PC) is associated with slower destruction of the adenine nucleotide pool ( summation operatorAd) and slower rate of anaerobic glycolysis during ischemic stress. These changes are concordant with the preconditioned state, supporting an essential role of lowered energy demand in the cardioprotective mechanism of PC. Although pharmacological PC induced by the activation of mitochondrial K(ATP) channels also limits infarct size, its effect on energy metabolism during sustained ischemia is unknown. Using metabolite levels found at baseline and after a 15 min test episode of regional ischemia, the effect of a cardioprotective dose of diazoxide on metabolic features associated with PC was tested in barbital-anesthetized, open-chest dogs. Diazoxide (3.5 mg/kg at an intravenous rate of 1 mL/min) infused before a test episode of ischemia had no effect on baseline metabolic indices. However, during ischemic stress, treated hearts exhibited less destruction of ATP, less degradation of the summation operatorAd into nucleosides and bases, as well as less lactate production than control hearts subjected only to ischemic stress. Thus, diazoxide mimics the metabolic alterations observed in PC tissue. This supports the hypothesis that a reduction in energy demand, which is now equated with an increased ATP to ADP ratio in the sarcoplasm, is a critical component of the mechanism of cardioprotection in preconditioned myocardium. It is hypothesized that during PC or diazoxide treatment, the passage of the summation operatorAd into and out of the mitochondria is slowed, limiting the level of ATP available to the mitochondrial ATPase and preserving ATP and the total summation operatorAd. Altered ischemic mitochondrial metabolism plays an important role in establishing and maintaining the preconditioned state.
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PMID:Pharmacological preconditioning with diazoxide slows energy metabolism during sustained ischemia. 1865 Sep 95

We have sought evidence that arachidonic acid (AA) induces mitochondrial depolarization in isolated myocytes by a lipoxygenase (LOX)-dependent mechanism and that such depolarization might contribute to arrhythmogenesis following ischemia-reperfusion injury. A method was developed for measuring mitochondrial depolarization in isolated adult rat myocytes in suspension, using tetramethylrhodamine ethyl ester. The addition of AA to myocytes resulted in mitochondrial depolarization that was inhibited by the LOX inhibitor baicalein, by the reactive oxygen species (ROS) scavenger mercaptoproprionylglycine, and by the anion channel inhibitor diisothiocyanatostilbene-disulfonic acid (DIDS). AA induced mitochondrial uncoupling and mitochondrial ATPase activity in myocytes, but both were insensitive to baicalein. We conclude that the metabolic effect of AA in myocytes puts mitochondria into an energetically compromised state where membrane potential is easily changed by the DIDS-sensitive LOX/ROS-mediated opening of an inner membrane anion channel. In an in vivo anesthetized rat model of coronary artery occlusion, baicalein was found to strongly inhibit arrhythmias induced by ischemia-reperfusion injury. Arrhythmias following ischemia-reperfusion injury have been previously associated with DIDS-sensitive ROS-mediated mitochondrial depolarization, and free fatty acids including AA were previously found to accumulate during such injury. We therefore conclude that arrhythmias following ischemia-reperfusion injury might originate from mitochondrial depolarization mediated by LOX and AA.
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PMID:Role of arachidonic acid, lipoxygenase, and mitochondrial depolarization in reperfusion arrhythmias. 2043 53


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