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)

Creatine kinase is a sulfhydryl containing enzyme that is particularly susceptible to oxidative inactivation. This enzyme is potentially vulnerable to inactivation under conditions when it would be used as a diagnostic marker of tissue damage such as during cardiac ischemia/reperfusion or other oxidative tissue injury. Oxidative stress in tissues can induce the release of iron from its storage proteins, making it an available catalyst for free radical reactions. Although creatinine kinase inactivation in a heart reperfusion model has been documented, the mechanism has not been fully described, particularly with regard to the role of iron. We have investigated the inactivation of rabbit muscle creatine kinase by hydrogen peroxide and by xanthine oxidase generated superoxide or Adriamycin radicals in the presence of iron catalysts. As shown previously, creatine kinase was inactivated by hydrogen peroxide. Ferrous iron enhanced the inactivation. In addition, micromolar levels of iron and iron chelates that were reduced and recycled by superoxide or Adriamycin radicals were effective catalysts of creatinine kinase inactivation. Of the physiological iron chelates studied, Fe(ATP) was an especially effective catalyst of inactivation by what appeared to be a site-localized reaction. Fe(ICRF-198), a non-physiological chelate of interest because of its putative role in alleviating Adriamycin-induced cardiotoxicity, also catalyzed the inactivation. Scavenger studies implicated hydroxyl radical as the oxidant involved in iron-dependent creatine kinase inactivation. Loss of protein thiols accompanied loss of creatine kinase activity. Reduced glutathione (GSH) provided marked protection from oxidative inactivation, suggesting that enzyme inactivation under physiological conditions would occur only after GSH depletion.
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PMID:Free radical inactivation of rabbit muscle creatinine kinase: catalysis by physiological and hydrolyzed ICRF-187 (ICRF-198) iron chelates. 783 53

Calcium-induced calcium release (CICR) from sarcoplasmic reticulum (SR) may contribute to calcium depletion of SR during the infusion of cardioplegic solution, which may protect the intracellular calcium overload observed during myocardial reperfusion. We have, therefore, investigated (1) the ability of ryanodine-containing cardioplegic solution to enhance myocardial protection and (2) the influence of diltiazem, L-type calcium channel blocker, on the ryanodine-enhanced cardioprotective effect in the isolated working rat heart. Hearts (n = 6-8/group) from male Wistar rats were aerobically (37 degrees C) perfused (20 min) with bicarbonate buffer (Ca2+ = 2.4 mM). This was followed by a 3 min infusion of St. Thomas' Hospital cardioplegic solution containing (1) 0 nmol/L of ryanodine or (2) 1.75 nmol/L of ryanodine combined with various concentrations of diltiazem (0, 0.13, 0.25 and 0.50 mumol/L). Hearts were then subjected to 40 min of normothermic (37 degrees C) global ischemia and 35 min of reperfusion (15 min Langendorff, 20 min working). (1) The recovery of aortic flow (%AF) was 52.2 +/- 3.5% in the ryanodine-free group. (2) %AF was 72.0 +/- 1.4%, 50.0 +/- 2.6*, 61.7 +/- 3.2* and 58.3 +/- 2.8*% in the 0, 0.13, 0.25 and 0.50 mumol/L diltiazem groups, respectively (*p < 0.05 vs the 0 mumol/L diltiazem group). Creatine kinase (CK) leakage during Langendorff reperfusion was less in the 0 mumol/L diltizaem (plus 1.75 nmol/L ryanodine) group than the ryanodine-free group.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Diltiazem abolishes the effect of ryanodine in St. Thomas' Hospital cardioplegic solution on the post-ischemic functional recovery]. 788 56

The benefit of cardioplegic cardiac arrest for the protection of immature myocardium is controversial. We therefore investigated the efficacy of (1) topical hypothermia alone, (2) slow cooling by coronary perfusion hypothermia, and (3) cardioplegic cardiac arrest for the protection of isolated immature rats hearts (28 days) during 8 hours of global ischemia at 10 degrees C. The study was conducted in hearts from rats that were kept hypoxemic by lifelong exposure to simulated high altitude. Left ventricular function, endothelial function, the metabolic status, and the extent of myocardial injury were all assessed. Topical hypothermia provided superior protection in hypoxic hearts, with recovery of the maximum developed left ventricular pressure by 70.6% +/- 18.0% (mean +/- standard deviation) of its preischemic value (p < 0.01 versus slow cooling and versus cardioplegic protection). The same pattern of recovery was observed among control hearts. The degree of recovery of endothelial function after sole topical hypothermia measured 54% +/- 36% in hypoxic hearts and 62% +/- 37% in control hearts, but was not recordable in any of the other groups. Creatine kinase leakage and the myocardial high-energy content did not differ significantly among any of the groups. Rapid cooling by topical hypothermia alone provides superior protection in chronic hypoxic, immature rat hearts versus the protection conferred by slow cooling. St. Thomas' Hospital cardioplegic solution II does not afford additional protection. Endothelial injury caused by cold asanguineous perfusates, including cardioplegia, interferes with the recovery of vascular function, which, in turn, may limit mechanical function.
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PMID:Protection of the chronic hypoxic immature rat heart during global ischemia. 788 15

The efficacy of increasing glycolysis during ischemia for enhancing the salutary effects of reperfusion was evaluated in isolated perfused rabbit hearts subjected to low-flow ischemia followed by reperfusion. Control hearts were perfused with buffer containing 0.4 mM palmitate, 5 mM glucose, and 70 mU/l insulin. Additional groups of hearts were perfused with double glucose/insulin and 1 mM dichloroacetate or were subjected to substrate priming to increase preischemic glycogen content. Ischemic contracture was completely prevented in hearts perfused with high glucose/insulin and was delayed markedly by either dichloroacetate or enhanced preischemic glycogen [45 +/- 14 and 31 +/- 20 min, respectively; P < 0.01 each vs. control (11 +/- 10 min)] and inversely related to the rate of lactate production. With reperfusion, recovery of developed pressure was 56 +/- 23% of baseline in control hearts, 90 +/- 8% in hearts receiving high glucose/insulin, 92 +/- 5% in hearts receiving dichloroacetate, and 79 +/- 19% in hearts with increased glycogen (P < 0.05 each vs. control hearts). Creatine kinase release was reduced by > 55% in treated hearts. Thus enhancement of glycolysis by diverse mechanisms during ischemia decreased ischemic damage and improved the recovery of contractile function with reperfusion.
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PMID:Rate of glycolysis during ischemia determines extent of ischemic injury and functional recovery after reperfusion. 797 9

Ischemic preconditioning has not been investigated in a clinically relevant model of hypothermic multidose cardioplegia arrest. Using isolated rabbit hearts perfused on a Langendorff apparatus, ischemic preconditioning was investigated as an adjunct to crystalloid cardioplegia during a 2.5-hour ischemic period at 15 degrees C. After baseline functional data were obtained, ischemic preconditioning was induced with either 1 minute or 5 minutes of normothermic ischemia, followed by 5 minutes of reperfusion before the arrest period. Control hearts underwent no ischemic preconditioning. The control hearts exhibited a decrement in both the peak developed pressure and diastolic function, as measured by the slope of the diastolic pressure-volume relationship, of from 107 +/- 2 to 68 +/- 7 mm Hg (p < 0.005) and from 0.99 +/- 0.2 to 2.95 +/- 0.44 mm Hg/0.1 mL (p < 0.005), respectively. Hearts exposed to either 1 or 5 minutes of normothermic ischemia showed no significant change in the slope of the diastolic pressure-volume relationship. Hearts exposed to 1 or 5 minutes of normothermic ischemia also had a significant decrease in the peak developed pressure of from 107 +/- 6 to 92 +/- 2 mm Hg and from 102 +/- 3 to 85 +/- 4 mm Hg, respectively (p < 0.05). However, ischemic preconditioning brought about a significant improvement in the postischemic peak developed pressure, as opposed to that seen for the control hearts (p < 0.05). Creatine kinase washout was significantly higher in the control hearts only. High-energy phosphate levels, lactate levels, the percentage wet weight, and tissue creatine phosphate levels were not significantly different among the groups.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ischemic preconditioning improves preservation with crystalloid cardioplegia. 797 79

Brief periods of ischemia have been suggested to protect against myocardial injury caused by a subsequent episode of prolonged ischemia and reperfusion. However, the protective effects of brief ischemic periods against myocardial dysfunction after prolonged myocardial ischemia are controversial. To examine whether the protective effects of brief ischemic episodes relate to the extent of prior ischemic events, isolated rat hearts were subjected to either no preischemia (group A); one 5-minute episode of preischemia and 10 minutes of reperfusion (group B); or two 1-minute episodes of ischemia, each followed by 5 minutes of reperfusion (group C). All hearts were then subjected to 15 minutes of total ischemia and 10 minutes of reperfusion. In group A, after 10 min of reperfusion coronary perfusion pressure (CPP) was 31% +/- 10% (mean +/- SEM) higher than the control value, peak force of cardiac contraction (FCC) was 64% +/- 5% lower, and heart rate was 18% +/- 3% lower. In group B, CPP increased 26% +/- 6%, FCC fell 58% +/- 7%, and heart rate decreased 22% +/- 8% (group B vs group A, P value not significant) after ischemia and reperfusion. In group C, CPP increased 23% +/- 7%, FCC decreased 57% +/- 8%, and heart rate fell 8% +/- 4% on reperfusion (group C vs groups A and B, P value not significant). Creatine kinase (CK) was measured in the hearts from different groups and was found to be similar. Release of the adenosine triphosphate (ATP) metabolites hypoxanthine, inosine, and adenosine was also not different in the coronary effluents of the three groups of hearts.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Failure of brief ischemic episodes to protect against myocardial dysfunction caused by ischemia and reperfusion in isolated rat hearts. 798 1

Calcium release from sarcoplasmic reticulum (SR) may contribute to the intracellular calcium overload observed during myocardial ischemia and reperfusion. We have therefore investigated the ability of ryanodine to enhance myocardial protection when given before ischemia or during reperfusion in the isolated working rat heart. Hearts (n = 6-9/group) from male Wistar rats were aerobically (37 degrees C) perfused (20 min) with bicarbonate buffer (Ca2+ = 2.4 mM). In the first series of studies, this was followed by a 3 min infusion of St Thomas' Hospital cardioplegic solution containing various concentrations of ryanodine. Hearts were then subjected to 38 min of normothermic (37 degrees C) global ischemia and 35 min of reperfusion (15 min Langendorff, 20 min working). The recoveries of aortic flow (%AF) were 50.3 +/- 2.5% in the ryanodine free controls versus 55.2 +/- 5.8, 72.0 +/- 1.3 (p < 0.05), 61.0 +/- 4.3, 51.8 +/- 5.1 and 32.1 +/- 5.0 (p < 0.05)% in the 0.88, 1.75, 2.13, 2.50 and 10.00 nM ryanodine groups, respectively. Creatine kinase (CK) leakage during Langendorff reperfusion was reduced in the 1.75 nM group but was similar to control in all other groups. In the second series of studies, 3 min of cardioplegia without ryanodine and 38 min of ischemia (37 degrees C) were followed by 15 min of Langendorff reperfusion with 0, 0.09, 0.18, 0.88 or 1.75 nM ryanodine, %AF was 59.3 +/- 3.3%, 54.7 +/- 3.3, 53.8 +/- 3.5, 38.4 +/- 8.9 (p < 0.05) and 33.3 +/- 5.8 (p < 0.05)% in the 0, 0.09, 0.18, 0.88 and 1.75 nM ryanodine groups, respectively. CK leakage tended to increase dose-dependently.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Sarcoplasmic reticular calcium release and myocardial protection--effect of ryanodine on myocardial ischemia and reperfusion-induced injury]. 817 88

We designed an experiment to compare single-dose versus multidose cardioplegia (calcium 0.3 mmol/L) in neonatal rabbit hearts 1, 4 and 6 weeks of age at 25 degrees C and 32 degrees C. Isolated hearts had a stabilization period of retrograde perfusion, a working period, a period of ischemia with single or multidose cardioplegia, reperfusion, and a final working period. We measured hemodynamic recovery, creatine kinase during reperfusion, and coronary vascular resistance during administration of the cardioplegic solution. One-week and 4-week-old hearts exhibited better recovery with single-dose than with multidose cardioplegia. Six-week-old hearts, on the other hand, showed better recovery with multidose cardioplegia. Four-week-old hearts at 25 degrees C showed increased creatine kinase release with multidose cardioplegia. The 6-week-old hearts tended toward lower creatine kinase release with multidose cardioplegia. Coronary vascular resistance rose with subsequent administrations in 1-week and 4-week-old hearts at 25 degrees C but did not rise in 1- and 4-week-old hearts at 32 degrees C or in 6-week-old hearts at either temperature. On the basis of hemodynamic recovery, single-dose cardioplegia appears to provide better protection than multidose cardioplegia to 1- and 4-week-old isolated rabbit hearts. Once the rabbit has reached 6 weeks of age, multidose cardioplegia has some advantage over single-dose cardioplegia, similar to the findings in adult hearts. Creatine kinase release and coronary vascular resistance data corroborate the hemodynamic findings.
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PMID:Single-dose versus multidose cardioplegia in neonatal hearts. 819 97

Immobilization of the rabbit knee in extension has previously been shown to damage the vastus intermedius profundus (VIP) muscle. To examine the mechanism of the early stages of the muscle damage, the authors studied creatine kinase activity in serum, and both light and electron microscopic changes in the affected muscle. The right knee was immobilized in an extended position using a splint, and thigh muscles were removed at various intervals, up to 48 hours after immobilization. The left hindlimb served as a control. Creatine kinase levels in serum rose ten hours after the onset of the immobilization. The enzyme levels reached a substantial peak by 24 hours, and plateaued thereafter. Light microscopic changes were not observed within 48 hours, but in electron microscopy distinct mitochondrial swelling and crystal abnormalities were seen as early as ten hours. The ultrastructural changes of mitochondria remained constant for up to 36 hours and decreased thereafter. At 48 hours of immobilization, also myofibrillar disorganization was seen. It appears that immobilization of the rabbit knee in extension rapidly leads to signs of remarkable damage to the VIP muscle. These suggest leakage of the cell membrane and metabolic disturbances. The ultrastructural changes observed share common features with muscle damage caused by ischemia, uncoupling agents, and inherited mitochondrial myopathies.
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PMID:Early muscle changes after immobilization. An experimental study on muscle damage. 824 49

Creatine kinase (CK) is normally found at high levels in muscle and brain and catalyzes the reaction phosphocreatine (PCr) + MgADP + H+<==>creatine (Cr) + MgATP. CK is not normally found at high levels in liver. A line of transgenic mice that express high levels of the BB-dimer of CK (CKB) in liver has allowed us to assess the role of CKB during periods of low oxygen stress. During 40 min of ischemia of normal perfused livers at 25 degrees C, ATP levels are depleted, and pH decreases to 6.6. pH recovers to a preischemic level after 30 min of reperfusion of normal livers; however, P(i) levels are significantly higher and ATP levels significantly lower than preischemic values. In transgenic liver with an initial PCr-to-ATP ratio of 4.5, ATP levels are maintained until PCr is markedly depleted. pH remains at preischemic levels for 16 min of ischemia of transgenic livers. During this length of ischemia in normal livers, pH has dropped to 6.9. pH, P(i), and ATP levels return to preischemic values within 30 min of reperfusion in transgenic livers containing PCr and CK. During 90 min of hypoxia of normal perfused livers at 37 degrees C, ATP is depleted. After 15 min of hypoxia of normal livers, there is a significant increase in the release of lactate dehydrogenase (LDH). In transgenic livers, ATP is maintained, and no increase in LDH release is observed for up to 90 min, depending on the level of PCr before hypoxia. These results demonstrate the role of CKB in buffering ATP levels and regulating intracellular pH during periods of low oxygen stress.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phosphocreatine protects transgenic mouse liver expressing creatine kinase from hypoxia and ischemia. 827 16


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