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 effect of ischemia on synthesis of myocardial proteins was investigated using a model of perfusion in which low levels of coronary flow were provided to paced hearts worked against a closed aortic outflow tract. These conditions rapidly produced ischemia and ventricular failure, as evidence by reduced coronary flow, increased left atrial pressure, and decreased pressure development. Protein synthesis was inhibited in a subsequent 1-hour period, during which a minimal coronary flow was maintained by retrograde perfusion. ATP, GTP, and creatinine phosphate were depleted in ischemic hearts and AMP accumulated. Production and accumulation of lactate within the tissue increased, whereas palmitate uptake was inhibited. The inhibition of protein synthesis was not associated with reduced levels of intracellular amino acids. During ischemia, decreased levels of ribosomal subunits as compared to paced or unpaced aerobic hearts suggested that peptide chain elongation was slow relative to initiation. Provision of insulin further reduced subunit levels but did not increase protein synthesis, suggesting that the hormone did not prevent inhibition of peptide chain elongation in energy-poor hearts.
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PMID:Effects of anoxia and ischemia on protein synthesis in perfused rat hearts. 126 87

The Na+/Ca2+ overload inhibitor R 56865 (N-[1-[4-(4-fluorophenoxy)-butyl]-4-piperidinyl)-N-methyl-2- benzothiazolamine) has been reported to prevent or attenuate ischemia- as well as ouabain-induced cellular sodium and calcium load. We investigated the potency of this compound in preventing mechanical, biochemical, and ultrastructural consequences of ouabain (OUA) intoxication in isolated rabbit heart. The protective effect of the digitalis antidote phenytoin (PHT) on the consequences of ouabain intoxication was examined for comparison. In isolated perfused rabbit heart, OUA (0.4 microM) caused an increase in left ventricular end-diastolic pressure (LVEDP) that was accompanied by depletion of high-energy phosphates (80% less than in control), accumulation of tissue lactate (12-fold) and damage of contractile elements and mitochondria. Accumulation of lactate was associated with a decrease in oxygen consumption by the isolated perfused heart. R 56865 (1.0 microM) and phenytoin (60 microM) prevented increase in LVEDP, breakdown of the energy-rich phosphates creatine phosphate (CrP) and ATP, accumulation of lactate, and morphologic changes induced by OUA. The above-mentioned toxic effects of OUA are interpreted as consequences of mitochondrial failure finally leading to breakdown of the oxidative phosphorylation. Thus, we conclude that the protective action of both compounds, R56865 and PHT, may be attributed to prevention or attenuation of mitochondrial failure due to OUA-induced disturbance of ion homeostasis.
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PMID:Effects of R 56865 and phenytoin on mechanical, biochemical, and morphologic changes during ouabain intoxication in isolated perfused rabbit heart. 127 87

We assessed whether local inhibition of myocardial converting enzyme by captopril and zofenopril reduces the functional and metabolic damage caused by ischemia and reperfusion. First we investigated the effects of zofenopril and captopril on the mechanical function, cellular redox state, and norepinephrine (NE) content of isolated and aerobically perfused rabbit hearts. Both drugs failed to modify the myocardial redox state. At concentrations > 10(-6) M, zofenopril, but not captopril, caused a reduction in myocardial NE content. At 10(-4) M, both drugs caused a reduction in developed pressure and an increase in diastolic pressure and release of creatine phosphokinase (CPK). Second we investigated their effects on ischemic and reperfused myocardium. Both drugs exerted a cardioprotection; zofenopril was always more potent than captopril. Recovery of developed pressure on reperfusion improved, and peak release of NE was reduced, as was release of CPK. Calcium homeostasis and mitochondrial function were maintained. Captopril had no effect on occurrence of oxidative stress during reperfusion, whereas zofenopril reduced it. In hearts treated with the converting enzyme inhibitors, peak release of NE was correlated to mitochondrial calcium content, production of ATP, and recovery of mechanical function on reperfusion. These data suggest that the cardioprotective effect of zofenopril and captopril is independent of hemodynamic changes or reduction of the toxicity of oxygen free radicals and that it could be related to a reduction in release of NE.
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PMID:Protection of the ischemic myocardium by the converting-enzyme inhibitor zofenopril: insight into its mechanism of action. 128 Jul 30

The objective of this study was to determine whether ATP-dependent potassium channel activation is involved in the mechanism by which nicorandil reduces postischemic contractile dysfunction produced by a brief period of ischemia (myocardial stunning). Barbital-anesthetized dogs were subjected to 15-min left anterior descending (LAD) coronary artery occlusion followed by 3-h reperfusion. Saline or nicorandil (100 micrograms/kg + 25 micrograms/kg/min) were infused 15 min before and throughout occlusion with or without addition of the KATP channel antagonist, glibenclamide 0.3 mg/kg as an intravenous (i.v.) bolus. Regional myocardial blood flow was measured by radioactive microspheres, and left ventricular (LV) segment function was measured by sonomicrometry. There were no significant differences between the groups in area-at-risk size or collateral blood flow. In contrast, nicorandil significantly reduced mean aortic blood pressure (BP) and the rate-pressure product (RPP) which persisted throughout the occlusion period. In addition, nicorandil markedly accelerated recovery of segment shortening in the ischemic/reperfused region as compared with control dogs. Pretreatment of dogs with glibenclamide blocked none of the hemodynamic effects of nicorandil, but it did prevent improvement in reperfusion segment function. The small dose of glibenclamide used had no effect on hemodynamics or the degree of stunning. Thus, these results suggest that nicorandil attenuates stunning in anesthetized dogs by a direct cardioprotective effect as a result of KATP channel activation in ischemic myocardium.
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PMID:Nicorandil attenuates myocardial dysfunction associated with transient ischemia by opening ATP-dependent potassium channels. 128 Jul 39

This article attempts correlating changes in cellular energy metabolism, acid-base alterations, and ion homeostasis in ischemia and other conditions. It is emphasized that loss of ion homeostasis, with thermodynamically downhill fluxes of K+, Ca2+, Na+, Cl-, and H+, occurs because energy production fails and (or) ion conductances are increased. In ischemia, energy failure is the leading event but, in hypoglycemia, activation of ion conductances is what precipitates energy failure. The initial event is a rise in K+ e, at least in part caused by activation of K+ conductances modulated by Ca2+ or ATP/ADP ratio. Secondarily, this leads to release of excitatory amino acids and massive activation of unspecific cation (and anion) conductances. Production of H+ occurs in states characterized by energy failure (ischemia and hypoxia) or by alkalosis (hypocapnia and ammonia accumulation). H+ equilibrates between intra- and extra-cellular fluid via nonionic diffusion of lactic acid, and transmembrane fluxes of H+ or HCO3- via ion channels. Since the relationship between lactate and either pHi or pHe is linear, there are no abrupt pH shifts explaining why hyperglycemia worsens ischemic damage. The reversible insults seem to induce a sustained stimulation of H+ extrusion from cells giving rise to intracellular alkalosis and extracellular acidosis.
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PMID:Coupling among changes in energy metabolism, acid-base homeostasis, and ion fluxes in ischemia. 128 29

Reperfusion of the heart 30 min. after ischemia causes slight recovery of contractility and content of macroergic compounds in the myocardium tissue. Recovery of perfusion by the hypercalcium medium (0.05 mol/l) improves metabolism of the myocardium 30 min after ischemia. However, further perfusion by solution with physiological content of Ca2+ is followed by the development of the myocardium contracture, essential decrease in extracellular concentration of ATP and phosphocreatine. An increase in the extracellular sodium concentration and addition of macroergic compounds (ATR, phosphocreatine) adenosine, when reperfusing the heart by hypocalcium solution, improve the postischemic state of the myocardium and protect it from injuries during the following recovery of physiological Ca2+ content in the extracellular medium.
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PMID:[A decrease in cardiac sensitivity after ischemia to a change in the extracellular concentration of calcium ions]. 128 84

In order to investigate the energetic status of the aged heart during ischemia and reperfusion we perfused female Wistar rats 6, 12 and 24 month old. The hearts were subjected to 15 min of global total ischemia plus 30 min of reperfusion. NMR spectra were collected during the entire experimental period to have the in vivo monitoring of the changes in intracellular pH and intracellular ATP, PCr and Pi contents. In the first 8 min of ischemia the fall of pH was similar in the 3 groups of rats, while at the end of the ischemic period the young rat hearts showed an intracellular pH significantly lower than aged rat hearts. At the end of reperfusion, ATP and PCr contents appeared significantly higher in the adult and aged hearts as compared to the young. The Pi content, on the contrary, was significantly lower in aged than young rat hearts. We suggest that the hearts of adult and aged animals, at the end of reperfusion, showed larger energetic recovery, in our experimental conditions of brief ischemia, than young hearts.
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PMID:[A 31P-NMR spectroscopic study of the changes in energy metabolism induced by cardiac ischemia and reperfusion in rats of different ages]. 129 70

Physiological parameters, rates of mitochondrial respiration, high energy phosphate levels and creatine phosphokinase (CPK) activity were investigated in the hearts from control and alloxan-induced diabetic rabbits before and after 40-min total ischemia and reperfusion. Diabetic hearts demonstrated significant decreases in the rates of contraction (+dP/dt) and relaxation (-dP/dt), heart rates and cardiac work compared to control hearts. Determination of mitochondrial respiration rates in saponin-skinned fibers showed a low mitochondrial respiratory function in diabetic hearts. It was found that the ATP and ADP levels and the total and mitochondrial isoenzyme activities of CPK in diabetic hearts were lowered in comparison with control. A post-ischemic recovery of cardiac performance for diabetic hearts was better than in controls. After reperfusion diabetic hearts had increased ATP levels. The data obtained demonstrate some abnormalities of both cardiac performance and energy metabolism in the hearts of diabetic animals and a decreased sensitivity of the latter to ischemic injury.
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PMID:[Energy metabolism and contractile function of the heart in diabetic cardiomyopathy: effect of ischemia and reperfusion]. 129 59

An electron microscopic study of heart muscle tissue exposed to six hours ischemia and prepared according to the low denaturation embedding technique revealed a structural modification confined to the mitochondrial cristae. The modification consisted of a removal of Krebs cycle enzymes from the cristae. Reperfusion of the ischemic tissue after four hours ischemia led to extensive breakdown of the mitochondrial structure and contractility could not be restored. However, when after six hours ischemia the ischemic tissue was reperfused with blood, the composition of which had been modified to stimulate mitochondrial function, no additional structural changes were observed and contractility was restored. The structural damage caused by reperfusion with non modified blood is explained by a loss of control of plasma membrane permeability caused by impaired ATP production which makes the ionic composition of the cytosol approach that of blood plasma, stopping oxidative phosphorylation. A treatment to restore heart muscle function after long periods of ischemia and after heart transplantation is proposed. The structural damage revealed that the Krebs cycle and the respiratory chain enzymes are associated according to a regular periodic pattern and that the enzyme molecules are closely aggregated three-dimensionally. Earlier electron microscopic studies revealing massive structural deterioration of heart muscle cells already after 45 to 60 minutes ischemia leading to the conclusion that the cells are irreversibly damaged, is based on fixation artifacts caused by osmium fixation. This study has been carried out in collaboration with the research team of Gerald D. Buckberg at the Thoracic Surgery Division at University of California at Los Angeles.
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PMID:Information and misinformation regarding ischemia of heart muscle tissue. The cause of cell death during blood reperfusion and reactivation of heart muscle tissue after prolonged ischemia. 129 75

Ca2+ ions are often invoked as potential initiators of cardiac arrhythmias in pathophysiological situations which are associated with an increase of free [Ca2+]i. It is well documented that elevated [Ca2+]i may produce SR release of Ca2+ and oscillations of membrane potential, thereby leading to triggered or spontaneous ectopic activity. The relation among elevated free [Ca2+]i, electrical cell-to-cell coupling, conduction slowing, and reentrant arrhythmias is more speculative. If Ca2+ (e.g. in mechanically injured cells) has direct access to the cellular interconnections (gap junctions), rapid uncoupling occurs at [Ca2+]i which is even within the range of a normal contractile cycle. If cellular integrity is preserved and changes of [Ca2+]i are imposed by extracellular interventions, the effect of [Ca2+]i is critically dependent on pHi. At normal pHi, transcellular conductance remains normal even if [Ca2+]i is increased to bring the cells into a hypercontractile state (> 1-2 microM). At decreased pHi, rapid uncoupling develops at low [Ca2+]i. Comparison of the conduction delay between two cells (or conduction velocity in a simulated conducting medium) with the [Ca2+]i-mediated increase in coupling resistance suggests that the transition from normal conduction velocity to conduction block (a key event in re-entrant arrhythmias) occurs within a relatively narrow range of [Ca2+]i or pHi, almost like a threshold phenomenon. Major efforts have been made in recent years to assess the changes of electrical cell-to-cell coupling and [Ca2+]i in myocardial ischemia. Therefore, the discussion of the role of [Ca2+]i as a modulator of electrical coupling is made in this pathophysiological setting. Comparison of several studies indicate that cell-to-cell resistance and [Ca2+]i in ischemia increase at the same time (10-15 min after perfusional arrest). Since other potential uncoupling processes (delta ATP, delta Mg2+, amphiphilic metabolites, delta pHi) show a similar time-course, it is difficult to attribute cell-to-cell uncoupling in ischemia solely to an increase in [Ca2+]i. Both an initial decrease of membrane excitability and subsequent electrical cell-to-cell uncoupling characterize the early phase of ischemia. The first mechanism is assumed to be more important for the generation of conduction block and re-entry. However, Ca(2+)-induced cell-to-cell uncoupling may partially contribute to the second phase of the early ischemic arrhythmias and mark the transition from reversible to irreversible ischemic damage.
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PMID:The potential role of Ca2+ for electrical cell-to-cell uncoupling and conduction block in myocardial tissue. 129 7


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