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

The voltage- and time-dependent slow channels in the myocardial cell membrane are the major pathway by which Ca2+ ions enter the cell during excitation for initiation and regulation of the force of contraction of cardiac muscle. These slow channels appear to behave kinetically, on a population basis, as if their gates open, close, and recover more slowly than those of the fast Na+ channels. In addition, the slow channel gates operate over a less negative (more depolarized) voltage range. Tetrodotoxin does not block the slow channels, whereas the calcium antagonistic drugs, Mn2+, Co2+, and La3+ ions do. The slow channels have some special properties, including functional dependence on metabolic energy, selective blockade by acidosis, and regulation by the intracellular cyclic nucleotide levels. Because of these special properties of the slow channels, Ca2+ influx into the myocardial cell can be controlled by extrinsic factors (such as autonomic nerve stimulation or circulating hormones) and by intrinsic factors (such as cellular pH or ATP level). During transient regional ischemia, the selective blockade of the slow channels, which results in depression of the contraction and work of the afflicted cells, might protect the cells against irreversible damage by helping to conserve their ATP content. Reperfusion arrhythmias may be caused by the breakdown of this protective mechanism, in that, upon reperfusion, the Ca2+ slow channels may recover before the cells are capable of handling the greater Ca2+ influx (Fig. 20). As depicted in this figure, the Ca2+ slow channels may recover their function before the ATP level is sufficiently recovered to allow bail-out of the intracellular Ca2+. In addition, the generation of free radicals upon reperfusion may injure the Ca-ATPase and other enzymes involved in Ca2+ metabolism. The net effect of this would be to cause Ca2+ overload of the cells and SR, with subsequent delayed after-depolarizations (DADs) leading to triggered automaticity and arrhythmias. Following blockade of the fast Na+ channels in myocardial cells with TTX or by voltage-inactivating them in 25 mM (K)0, catecholamines, angiotensin-II, histamine, and methylxanthines rapidly allow the production of slowly-rising Ca2+-dependent action potentials by increasing the number of Ca2+ slow channels available for voltage activation and/or their mean open time. Concomitantly, these compounds rapidly elevate intracellular cyclic AMP levels, suggesting that cyclic AMP is somehow related to the functioning of the slow channels. Exogenous cyclic AMP produces the same effect, but much more slowly.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of calcium slow channels of cardiac muscle by cyclic nucleotides and phosphorylation. 245 7

Fluorescein-isothiocyanate dextran (FITC-dextran), a dye confined to the vascular space, was infused via the hepatic artery and portal vein into perfused livers from fed rats treated with diethylnitrosamine for 4 to 5 months. Fluorescence due to FITC-dextran was detected with fiberoptic microlight guides placed on surface nodules of about 5 mm in diameter. Nodules were categorized into groups with normal and compromised microcirculation based on their fluorescence following infusion of FITC-dextran. Similar results were obtained when nodules were classified based on reflectance of trypan blue. Despite compromised microcirculation, ATP and ADP levels as well as ATP/ADP ratios were comparable in both groups of nodules; however, AMP was elevated in FITC-dextran-negative nodules (i.e., those with compromised microcirculation). Nodules with compromised microcirculation also contained higher glucose and lactate levels than nodules that were well perfused; however, glycogen was five times lower than in FITC-dextran-positive nodules. Fasting reduced ATP/ADP ratios in poorly perfused nodules in comparison to well-perfused nodules. In perfused livers from fed rats where glycogen was high, however, ATP/ADP ratios and rates of ATP depletion during ischemia were the same in well-perfused and poorly perfused nodules. Products of glycogen breakdown (e.g., glucose and lactate) were elevated in nodules from livers of fed but not fasted rats. The results indicate that alteration of perfusion of hepatic nodules does not change ATP levels nor the capacity of nodules to utilize high energy phosphate during anoxia. Thus, near normal energy status is maintained from glycogen metabolism in poorly perfused nodules via glycolysis. Since basal ATP content and utilization is comparable in well and poorly perfused nodules, compromised energy status is unlikely to explain selection of nodules that regress to near normal hepatocytes.
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PMID:Adenine nucleotides and carbohydrates in subpopulations of hepatic nodules with normal and compromised microcirculation. 247 May 3

Mammalian brain glycogen is adequate to support oxidative metabolism for several minutes. The present studies were done primarily to develop the guinea pig hippocampal slice as a model for studying the function and regulation of that glycogen. Slice glycogen falls to 6 nmol/mg dry wt. during the first hour of incubation at 36 degrees C but during the next 3 h recovers to 20 nmol/mg dry wt., similar to in situ values. Glycogen concentration in the dentate gyrus molecular layer is double its value in the whole hippocampal slice, suggesting its distribution is related to metabolic demand. When both glucose and oxygen are removed from the medium, glycogen and ATP fall to 50% within 6 min. The glycogen fall is unaffected by prolonged calcium depletion or by 3-isobutyl 1-methylxanthine, an adenosine antagonist. It is markedly slowed by preincubating the slice with creatine, which also slows the fall in ATP. It is concluded that ATP breakdown and subsequent increased 5'-AMP is activating glycogen mobilization in this in vitro model of ischemia.
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PMID:Regulation of glycogen in the dentate gyrus of the in vitro guinea pig hippocampus; effect of combined deprivation of glucose and oxygen. 247 Oct 20

High energy phosphate levels are depressed following global ischemia and require several days to completely recover. Short-term methods to enhance ATP recovery have included infusion of ATP precursors, inhibition of enzymes that catabolize AMP, and membrane transport stabilization. Several precursors have been used to augment adenine nucleotide synthesis including adenosine, inosine, adenine, and ribose. Because of the short-term nature of previous experiments, recovery had been incomplete and the effects in the intact animal unknown. The purpose of this study was to determine the effects of ribose infusion in a long-term model of global ischemia and attempt to identify the precursor which limits myocardial ATP regeneration in the intact animal. Global myocardial ischemia (20 min, 37 degrees C) was produced in dogs on cardiopulmonary bypass. With reperfusion either ribose (80 mM) in normal saline or normal saline alone was infused at 1 ml/min into the right atrium and the animals were followed for 24 hr. Ventricular biopsies were obtained through an indwelling ventricular cannula prior to ischemia, at the end of ischemia, and 4 and 24 hr postischemia and analyzed for adenine nucleotides and creatine phosphate levels. Radiolabeled microspheres were used to measure myocardial and renal blood flows and no significant difference was found between ribose-treated control groups. In both groups, myocardial ATP levels fell by at least 50% at the end of ischemia. No significant ATP recovery occurred after 24 hr in the control dogs, but in the ribose-treated animals, ATP levels rebounded to 85% of control by 24 hr.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Enhanced high energy phosphate recovery with ribose infusion after global myocardial ischemia in a canine model. 249 8

The influence of pressure-controlled postischemic reperfusion (Rp) on functional and metabolic parameters in hearts of sham-operated rats and hypertrophied hearts of rats with aortic constriction were studied. Hypertrophied hearts are considered to be more susceptible to ischemia. The hearts were perfused in the Langendorff-technique for thirty minutes at 35 degrees C with Krebs-Henseleit bicarbonate buffer at a perfusion pressure (PP) of 75 mmHg and for five minutes at 15 degrees C with St. Thomas' Hospital cardioplegic solution at a PP of 60 mmHg. After a period of global ischemia of forty minutes' duration at 15 degrees C, reperfusion was started either abruptly (aRp: PP 75 mmHg immediately) or gently (gRp: PP 75 mmHg within thirty minutes); it lasted for forty-five minutes. Intraventricular peak systolic pressure (ISP) was monitored and energy-rich compounds (ATP, ADP, AMP, CrP, free Cr) were analyzed. In normal hearts, metabolic recovery was not affected by the mode of reperfusion, but functional recovery (ISP) averaged 88% of the preischemic control value after gRp as compared with 73% after aRp. In hypertrophied hearts, gentle reperfusion ameliorated both metabolic and functional recovery. At forty-five minute recovery, CrP averaged 5.1 mumol/g ww after aRp and 6.6 mumol/g ww after gRp (p less than 0.01), and ISP amounted to 73% of the preischemic control after aRp and to 85% after gRp.
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PMID:Pressure-controlled reperfusion improves postischemic recovery of LV-hypertrophied rat hearts. 252 79

Acute myocardial ischemia maintained for 30 and 60 min with subsequent reperfusion did not induced alterations in the cyclic AMP-mediated phosphorylation capacity of phospholamban and troponin I. Inotropic stimulation of the normal heart with 0.1/uM isoprenaline for 2 min resulted in a simultaneous P-incorporation into phospholamban and troponin I to 44.4 +/- 7.5 pmoles P/mg protein and 42.4 +/- 2.9 pmoles P/mg protein, respectively, assayed by a standardized back-phosphorylation procedure. The adrenergic responsiveness, however, was markedly reduced in the time course of ischemia. After an ischemic period of 60 min the adrenergic-stimulated phosphorylation of phospholamban was diminished to 41 per cent of the control value, whereas the increase of troponin I phosphorylation was completely lost. This differential effect can be discussed in terms of the existence of cytosolic compartments for cA, possessing different lability to ischemic injury of cardiac cells. After post-ischemic reperfusion the isoprenaline responsiveness of the phosphorylation of phospholamban and troponin I was found to be normal demonstrating a reversibility at the level of two important regulator proteins, if the transient ischemia do not exceed 60 min period.
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PMID:Phosphorylation of phospholamban and troponin I in the ischemic and reperfused heart: attenuation and restoration of isoprenaline responsiveness. 252 30

The present study was designed to examine the relation between the loss of Ca2+ uptake activity and the change of protein phosphorylation in sarcoplasmic reticulum from ischemic myocardium. Ischemic (0.5, 1 and 2 h duration) and non-ischemic tissue samples were taken from the coronary-ligated porcine left ventricle and sarcoplasmic reticulum fractions were isolated. The membranes were tested for Ca2+ uptake and ATPase activities and phosphorylation of phospholamban. The in vitro 32P incorporation into phospholamban in the presence of cAMP plus the catalytic subunit of cyclic AMP dependent protein kinase became markedly reduced depending on the duration of ischemia. The activities of the Ca2+ pump (Ca2+ uptake and ATPase) were also decreased. The 32P incorporation into the myofibrillar component troponin I, which is also a specific substrate for catalytic subunit, was not affected by ischemia. The reduction of the Ca2+ pump activity correlated with the reduction of 32P incorporation into phospholamban. It is postulated that the ischemia induced inactivation of the Ca2+ pump is not only a consequence of specific loss of enzyme activity, but it is also caused by altered characteristics of phospholamban.
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PMID:Calcium transport and phospholamban in sarcoplasmic reticulum of ischemic myocardium. 252 77

We have evaluated the impact of inhibiting adenine nucleotide dephosphorylation on the metabolic and functional consequences of renal ischemia. Intramuscular injection of the ADP-analogue adenosine alpha, beta-methylene diphosphate (AMP-CP) achieved a 70% reduction in 5'-nucleotidase activity, as measured in crude extracts of rat kidney. AMPCP-treated animals had an increased residual nucleotide pool at the end of 45 min of ischemia compared with untreated rats. Assessment of renal ATP by 31P-nuclear magnetic resonance (31P-NMR) in vivo during reflow demonstrates the following: 1) higher rapid initial recovery of ATP (69.3 +/- 1.2 vs. 50.0 +/- 0.5% control value, P less than 0.005), 2) accelerated rate of ATP restoration (0.20 +/- 0.02 vs. 0.11 +/- 0.01% control/min, P less than 0.005), and 3) significantly enhanced renal ATP content after 120 min (93.6 +/- 2.0 vs. 63.1 +/- 0.7% control, P less than 0.005). Kidney function, as measured by the rate of inulin clearance 24 h after the insult, was also significantly improved in AMPCP-treated rats (725 +/- 50 vs. 313 +/- 28 microliters.min-1.100 g body wt-1). Thus inhibition of 5'-nucleotidase results in enhanced metabolic and functional recovery from a renal ischemic insult.
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PMID:Protection of the kidney against ischemic injury by inhibition of 5'-nucleotidase. 253 26

The effects of ischemia, reperfusion and hypoxia on the cardiac acetylcholine, choline, norepinephrine and cyclic AMP contents were investigated in isolated, spontaneously beating rat hearts perfused under constant pressure (100 cm H2O) with Krebs-Henseleit solution gassed with 95% O2-5% CO2. Acetylcholine, choline and norepinephrine were determined by high performance liquid chromatography with electrochemical detection. Cyclic AMP was determined by radioimmunoassay. One min reperfusion following 15 min ischemia (termination of perfusion) caused a significant decrease in both cardiac acetylcholine (P less than 0.05) and norepinephrine (P less than 0.01) contents, but had no significant effect on the cardiac norepinephrine/acetylcholine content ratio, or choline or cyclic AMP content. By contrast, 16 min ischemia did not significantly affect the cardiac acetylcholine, norepinephrine, choline or cyclic AMP content. Also, 16 min hypoxia (perfusion with Krebs Henseleit solution gassed with 95% N2 5% CO2) decreased the cardiac norepinephrine content significantly (P less than 0.01) and norepinephrine/acetylcholine content ratio slightly but not significantly. However, hypoxia had no significant effect on the cardiac acetylcholine, choline or cyclic AMP content. Pre-treatment with 10 microns atropine sulfate prevented the decrease in the cardiac acetylcholine content caused by reperfusion but caused a significant depletion in the cardiac norepinephrine content in the control (P less than 0.01) and ischemia (P less than 0.05) groups and a significant decrease in the norepinephrine/acetylcholine content ratio in all three groups (all, P less than 0.05). Extending the reperfusion period to 5 and 10 min following 15 min ischemia also caused a significant decrease in both cardiac acetylcholine and norepinephrine contents compared with the control groups. However, no significant difference in these contents was found between 1 min reperfusion group and 5 or 10 min reperfusion group. Twenty or 25 min ischemia alone did not significantly affect these contents. These findings suggest that reperfusion disturbs both the sympathetic and parasympathetic nervous systems in the heart and that pre-treatment with atropine adversely affects the balance of the autonomic nervous system.
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PMID:Effect of reperfusion on the cardiac acetylcholine and norepinephrine contents in rat hearts. 254 84

Adenine nucleotide metabolism is greatly altered by myocardial anoxia or ischemia, both of which induce depletion of ATP and of the total adenine nucleotide pool. The depletion occurs at variable rates depending upon the nature of the model and the severity and conditions of the injury. In ischemia, the decrease in both ATP and the adenine nucleotide pool is due to an inadequate rate of production of high-energy phosphate relative to the demand of the heart for energy. In the process of capturing the high-energy phosphate of ADP, AMP is produced via myokinase and is degraded to nucleosides and ultimately to bases. In the early phase of ischemia, ADO and INO are the chief metabolites produced. A small quantity of XAN and large quantities of HX accumulate with time until eventually HX replaces INO as the principal metabolite of the pool. The biology of myocardial ischemic cell damage in the dog heart is summarized with respect to the depletion of ATP and total adenine nucleotide pool. Myocytes can survive with about 25% of the ATP of control tissue but exhibit a variety of defects that persist for minutes to days. At the onset of irreversibility, the dead tissue invariably exhibits virtually no ATP and a 65% or greater depletion in the total adenine nucleotide pool. It is not known whether these changes in ATP and the pool are directly or indirectly related to the development of irreversibility. In any event, the transition to cell death appears to be gradual.
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PMID:Nucleotide metabolism and cellular damage in myocardial ischemia. 258 8


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