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

Dysfunctional sarcoplasmic reticulum (SR) is thought to be involved in the phenomenon of myocardial stunning. Adult (3 to 4 kg) and neonatal (5 to 7 day old) rabbit hearts were examined for structural SR alterations following ischemic damage and myocardial stunning induced by incubation in Ringer's lactate at 39 degrees C. SR protein yield in neonate hearts (but not adult hearts) significantly decreased (p = 0.01) following 30 minutes of ischemia. In addition, calcium ATPase activity was reduced in both adult p = 0.006) and neonatal (p = 0.02) ischemic hearts. Examination of SR proteins by gel electrophoresis indicated that the levels of several proteins were altered by ischemia. In adult hearts, decreased levels of proteins of 22.5, 31.5, 33, and 83 kilodaltons (kd) were observed. In newborn ischemic hearts, decreases in 29, 37.5, 82, and 83 kd proteins were detected. The quantitative changes in calcium ATPase levels and SR protein content may adversely affect myocardial excitation-contraction coupling and relaxation, contributing to dysfunction in myocardial stunning.
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PMID:Sarcoplasmic reticulum in globally stunned adult and newborn myocardium. 846 21

Myocardial contractile failure is a common cause of morbidity and mortality in patients with ischemic heart disease and inflammatory disorders such as sepsis. Recent research indicates that contractile failure is associated with dysregulation of cytoplasmic calcium levels in the myocyte. However, the specific biochemical alterations responsible for calcium dysregulation remain unclear. In a search for mechanisms which might explain the altered calcium regulation in cardiac cells during ischemia and sepsis, we discovered new roles for an intracellular peptide which regulates intracellular calcium and contractility in myocardial cells. The intracellular peptide carnosine improves contraction in the isolated rat heart and increases free intracellular calcium levels. It stimulates calcium release from the ryanodine calcium-release channel, inhibits calcium uptake by the sarcoplasmic reticulum calcium pump, and sensitizes the contractile proteins to calcium. We believe that this peptide represents a new intracellular messenger system for the regulation/modulation of intracellular calcium. Changes in levels of carnosine may play a role in the altered contractility seen during critical illness.
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PMID:Carnosine: a novel peptide regulator of intracellular calcium and contractility in cardiac muscle. 868 73

Interruption of cerebral blood flow leads to dissipation of ionic gradients as the consequence of ionic channel overstimulation and ionic pump failure. The aim of this work was to study the possible effects of ischaemia and ischaemia followed by reperfusion on biochemical properties of endoplasmic calcium pump and synaptosomal sodium pump and sodium/calcium exchanger. The results presented in this study showed that 15 minute ischaemia led to the inhibition of all three ionic transport systems, however in different degrees. 60 minute reperfusion following 15 minute ischaemia led to partial recovery of calcium pump and sodium/calcium exchanger. The activity of sodium pump was still significantly depressed. Ischaemia and ischemia followed by reperfusion did not affect kinetic parameters of calcium pump. On the other side, both ischaemia and ischaemia-reperfusion led to an increase of sodium pump affinity to ATP and a decrease of the enzyme affinity to potassium. The possible causes of the changes, as the alteration of membrane structure or altered enzymes phosphorylation are discussed in the study. In addition to the inhibitory effect of ischaemia-reperfusion injury, intracellular water accumulation, as the possible consequence of altered ion homeostasis, is documented by nuclear magnetic resonance (imaging).
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PMID:[The effect of ischemia and ischemia-reperfusion on ion transport systems]. 974 29

Several studies have shown that the protective effect of ischemic preconditioning (PC) is associated with decreased calcium release from the sarcoplasmic reticulum (SR). However, no study has yet demonstrated whether these changes are essential in the mechanism of PC. In order to investigate whether a functional SR was necessary for PC, we manipulated SR calcium handling using (i) 0.1microM ryanodine (RY), a concentration known to lock the SR calcium release channel in the open state and (ii) 50microM cyclopiazonic acid (CPA), a specific inhibitor of the SR calcium ATPase. Initial experiments confirmed that both RY and CPA eliminated the ability of the SR to accumulate calcium. Isolated rat hearts (n=6-7/group) were perfused normoxically for 30 min prior to either a further 40 min of perfusion [control (C)] or 4x[5 min ischemia (I) + 5 min reperfusion (R)] (PC). All hearts were then subjected to a further 40 min I + 40 min R. The C and PC protocols were then repeated in the presence of RY or CPA, introduced after 10 min of perfusion.(31)P-NMR was used to measure ATP, PCr, P(i)and intracellular pH. RY and CPA decreased developed pressure (DP) by 75% and 59%, respectively. Percentage recovery of LVDP was significantly higher in PC (72+/-8%), PC+RY (72+/-7%) and PC+CPA (49+/-7%) groups compared with their respective controls (43+/-7%, 47+/-7% and 10+/-4%) (P<0.05). Thus, PC remains protective in the presence of a SR unable to accumulate calcium, suggesting that the changes in SR calcium release are not essential in the mechanism of preconditioning.
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PMID:Is a functional sarcoplasmic reticulum necessary for preconditioning? 1096 37

Regulation of the Na/K ATPase by protein kinases is model-specific. We have observed a profound activation of the sarcolemmal Na/K ATPase during cardiac ischemia, which is masked by an inhibitor of the enzyme in the cytosol. The aim of these studies was to characterize the pathways involved in this activation in the Langendorff-perfused rat heart. Na/K ATPase activity was determined by measuring ouabain-sensitive phosphate generation by cardiac homogenates at 37 degrees C. In isolated sarcolemma, ischemia (30 min) caused a substantial activation of the Na/K ATPase compared with aerobic controls, which was abolished by perfusing the heart with staurosporine or H89. However, the alpha1 subunit of the Na/K ATPase was not phosphorylated during ischemia. The sarcolemmal protein phospholemman (PLM) was found associated with the Na/K ATPase alpha1 and beta1 but not alpha2 subunits, and PLM increased its association with the catalytic subunit of PKA following ischemia. In vitro 14-3-3 binding assays indicated that PLM was phosphorylated following ischemia. These results indicate that the ischemia-induced activation of the Na/K ATPase is indirect, through phosphorylation of PLM, which is an integral part of the Na/K ATPase enzyme complex in the heart. The role of PLM is analogous to phospholamban in regulating the sarcoplasmic reticulum calcium ATPase.
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PMID:Ischemia-induced phosphorylation of phospholemman directly activates rat cardiac Na/K-ATPase. 1459 63

Human hibernating myocardium (HHM) is characterized by reversible contractile dysfunction during chronic ischemia. A disturbed calcium-homeostasis is a decisive factor for reduced functional capacity in heart diseases. We therefore investigated calcium-handling proteins in HHM. In 12 patients suffering from multi-vessel coronary artery disease and contractile dysfunction with indication for bypass surgery, HHM was detected preoperatively by thallium scintigraphy, radionuclide ventriculography and dobutamine echocardiography. Transmural biopsies of these regions were taken and analyzed by immunohistochemistry and electron microscopy. Furthermore, SR-calcium ATPase (SERCA2a), phospholamban (PLN), the phosphorylated forms of PLN (PLN-Ser16, PLN-Thr17) as well as sodium-calcium exchanger (NCX) and ryanodine receptor (RyR2) were investigated by RT-PCR and Western-blotting. Additionally, SERCA2a activity was measured by an enzyme-coupled assay. In all patients complete functional recovery could be documented 3 months after revascularization by repeating all preoperative investigations. In HHM maximal SERCA2a activity was significantly reduced (HHM: 424.5 +/- 33.9, control: 609.0 +/- 48.5 nmol ATP mg protein(-1) min(-1), p <or= 0.05), whereas SERCA2a protein levels were unchanged. mRNA levels (HHM: 1.36 +/- 0.08 vs. control: 0.78 +/- 0.04, p <or= 0.05) and protein amount (HHM:1.67 +/- 0.14 vs. control: 1.00 +/- 0.04, p <or= 0.05) of PLN (A1) were increased resulting in an increased PLN:SERCA2a-ratio. PLN-Ser16 (HHM: 0.60 +/- 0.08 vs. control: 1.00 +/- 0.11, p <or= 0.05) and PLN-Thr17 (HHM: 0.63 +/- 0.11 vs. control: 1.00 +/- 0.06, p <or= 0.05) phosphorylation was significantly decreased. RyR2 and NCX showed no significant alteration. In HHM a decreased activity of SERCA2a due to an impaired phosphorylation of PLN contributes to contractile dysfunction. The increase in the relative ratio of PLN/SERCA2a leads to a decreased calcium affinity of SERCA2a.
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PMID:Reduced sarcoplasmic reticulum Ca2+ -ATPase activity and dephosphorylated phospholamban contribute to contractile dysfunction in human hibernating myocardium. 1631 12

Myocardial oxidative stress and Ca2+ overload induced by ischemia-reperfusion may be involved in the development and progression of myocardial dysfunction in heart failure. Xanthine oxidase, which is capable of producing reactive oxygen species, is considered as a culprit regarding ischemia-reperfusion injury of cardiomyocytes. Even though inhibition of xanthine oxidase by allopurinol in failing hearts improves cardiac performance, the regulatory mechanisms are not known in detail. We therefore hypothesized that allopurinol may prevent the xanthine oxidase-induced reactive oxygen species production and Ca2+ overload, leading to decreased calcium-responsive signaling in myocardial dysfunction. Allopurinol reversed the increased xanthine oxidase activity in ischemia-reperfusion injury of neonatal rat hearts. Hypoxia-reoxygenation injury, which simulates ischemia-reperfusion injury, of neonatal rat cardiomyocytes resulted in activation of xanthine oxidase relative to that of the control, indicating that intracellular xanthine oxidase exists in neonatal rat cardiomyocytes and that hypoxia-reoxygenation induces xanthine oxidase activity. Allopurinol (10 microM) treatment suppressed xanthine oxidase activity induced by hypoxia-reoxygenation injury and the production of reactive oxygen species. Allopurinol also decreased the concentration of intracellular Ca2+ increased by enhanced xanthine oxidase activity. Enhanced xanthine oxidase activity resulted in decreased expression of protein kinase C and sarcoendoplasmic reticulum calcium ATPase and increased the phosphorylation of extracellular signal-regulated protein kinase and p38 kinase. Xanthine oxidase activity was increased in both ischemia-reperfusion-injured rat hearts and hypoxia-reoxygenation-injured cardiomyocytes, leading to reactive oxygen species production and intracellular Ca2+ overload through mechanisms involving p38 kinase and extracellular signal-regulated protein kinase (ERK) via sarcoendoplasmic reticulum calcium ATPase (SERCA) and protein kinase C (PKC). Xanthine oxidase inhibition with allopurinol modulates reactive oxygen species production and intracellular Ca2+ overload in hypoxia-reoxygenation-injured neonatal rat cardiomyocytes.
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PMID:Allopurinol modulates reactive oxygen species generation and Ca2+ overload in ischemia-reperfused heart and hypoxia-reoxygenated cardiomyocytes. 1651 85

An important mechanism underlying cochlear hair cell (HC) susceptibility to hypoxia/ischemia is the influx of Ca(2+). Two main ATP-dependent mechanisms contribute to maintaining low Ca(2+) levels: uptake of Ca(2+) into intracellular stores via smooth endoplasmic reticulum calcium ATPase (SERCA) and extrusion of Ca(2+) via plasma membrane calcium ATPase (PMCA). The effects of the SERCA inhibitors thapsigargin (10 nM-10 microM) and cyclopiazonic acid (CPA; 10-50 microM) and of the PMCA blockers eosin (1.5-10 microM) and o-vanadate (1-5 mM) on inner and outer hair cells (IHCs/OHCs) were examined in normoxia and ischemia using an in vitro model of the newborn rat cochlea. Exposure of the cultures to ischemia resulted in a significant loss of HCs. Thapsigargin and CPA had no effect. Eosin decreased the numbers of IHCs and OHCs by up to 25 % in normoxia and significantly aggravated the ischemia-induced damage to IHCs at 5 and 10 microM and to OHCs at 10 microM. o-Vanadate had no effect on IHC and OHC counts in normoxia, but aggravated the ischemia-induced HC loss in a dose-dependent manner. The effects of eosin and o-vanadate indicate that PMCA has an important role to play in protecting the HCs from ischemic cell death.
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PMID:Effects of SERCA and PMCA inhibitors on the survival of rat cochlear hair cells during ischemia in vitro. 1770 70

This article examines the pathophysiology of lesions caused by focal cerebral ischemia. Ischemia due to middle cerebral artery occlusion encompasses a densely ischemic focus and a less densely ischemic penumbral zone. Cells in the focus are usually doomed unless reperfusion is quickly instituted. In contrast, although the penumbra contains cells "at risk," these may remain viable for at least 4 to 8 hours. Cells in the penumbra may be salvaged by reperfusion or by drugs that prevent an extension of the infarction into the penumbral zone. Factors responsible for such an extension probably include acidosis, edema, K+/Ca++ transients, and inhibition of protein synthesis. Central to any discussion of the pathophysiology of ischemic lesions is energy depletion. This is because failure to maintain cellular adenosine triphosphate (ATP) levels leads to degradation of macromolecules of key importance to membrane and cytoskeletal integrity, to loss of ion homeostasis, involving cellular accumulation of Ca++, Na+, and Cl-, with osmotically obligated water, and to production of metabolic acids with a resulting decrease in intra- and extracellular pH. In all probability, loss of cellular calcium homeostasis plays an important role in the pathogenesis of ischemic cell damage. The resulting rise in the free cytosolic intracellular calcium concentration (Ca++) depends on both the loss of calcium pump function (due to ATP depletion), and the rise in membrane permeability to calcium. In ischemia, calcium influx occurs via multiple pathways. Some of the most important routes depend on activation of receptors by glutamate and associated excitatory amino acids released from depolarized presynaptic endings. However, ischemia also interfers with the intracellular sequestration and binding of calcium, thereby contributing to the rise in intracellular Ca++. A second key event in the ischemic tissue is activation of anaerobic glucolysis. The main reason for this activation is inhibition of mitochondrial metabolism by lack of oxygen; however, other factors probably contribute. For example, there is a complex interplay between loss of cellular calcium homeostasis and acidosis. On the one hand, a rise in intracellular Ca++ is apt to cause mitochondrial accumulation of calcium. This must interfere with ATP production and enhance anaerobic glucolysis. On the other hand, acidosis must interfere with calcium binding, thereby contributing to the rise in intracellular Ca++.
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PMID:Pathophysiology and treatment of focal cerebral ischemia. Part I: Pathophysiology. (1992). 162 4

Luteolin, a naturally occurring polyphenol flavonoid, has demonstrated to exert myocardial protection effects. However, the mechanisms have not been fully elucidated. In the present study, we investigated whether luteolin pretreatment was associated with cardioprotection in a rat ischemia/reperfusion (I/R) model. Luteolin significantly not only restored contractility of the left ventricle, but also reduced the infarct size and lactate dehydrogenase leakage during I/R. In addition, luteolin pretreatment significantly improved cardiomyocyte shortening amplitude, decreased the apoptotic rate, upregulated Bcl-2 expression, downregulated Bax expression and raised the Bcl-2/Bax ratio under a simulated ischemia/reperfusion (SI/R) condition. Moreover, luteolin pretreatment increased protein kinase B (Akt) phosphorylation, phospholamban phosphorylation and the expression of sarcoplasmic reticulum calcium ATPase following SI/R. The phosphoinositide 3-kinase (PI3K)/Akt pathway is one of the most important intracellular survival signal pathways. To determine whether luteolin-induced cardioprotection was mediated by the PI3K/Akt pathway, we utilized the PI3K inhibitor LY294002. Inhibition of Akt activity markedly abolished luteolin-induced positive contraction and inhibition of apoptosis in SI/R cardiomyocytes. These results showed that luteolin inhibits apoptosis and improves cardiomyocyte contractile function at least partly through the PI3K/Akt pathway in SI/R.
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PMID:Luteolin inhibits apoptosis and improves cardiomyocyte contractile function through the PI3K/Akt pathway in simulated ischemia/reperfusion. 2193 51


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