Inhibitory effect of ketamine on phosphorylation of the extracellular signal-regulated kinase1/2 following brain ischemia and reperfusion in rats with hyperglycemia

To determine if the inhibitory effects of ketamine on the extracellular signal-regulated kinase (ERK) 1/2 are involved in reduction of the hyperglycemia-exaggerated cerebral ischemic lesion, rats with normoglycemia, hyperglycemia, or hyperglycemia supplemented with ketamine were subjected to 15 min of forebrain ischemia, and then, reperfusion for 0.5, 1, and 3h. Phosphorylation of ERK1/2 in the brain tissues was assessed by immunohistochemistry and Western blot analysis. In rats with normoglycemia, we demonstrated a moderate increase of the ERK1/2 phosphorylation in the cingulum cortex and hippocampus CA3 following an ischemic intervention. It quickly dropped to control levels after reperfusion for 0.5h. In rats with hyperglycemia, however, the increase of the ERK1/2 phosphorylation in these areas was significantly higher in all animals reperfused. The neuronal death, detected by the TdT-mediated-dUTP nick end labeling assays, was found in the cingulum cortex (5.23+/-2.34, per high power feild) and hippocampus CA3 areas (6.29+/-3.68, per 1mm(2)) in hyperglycemic group after reperfusion for 3h. With ketamine treatment, the ERK1/2 phosphorylation in cingulum cortex and hippocampus CA1 and CA3 areas was found to be the same as that in normoglycemia rats. Our results suggest that hyperglycemia may increase the ischemic insult through modulation of the signal transduction pathways involving ERK1/2. The inhibitory effects of ketamine on the hyperglycemia-activated ERK1/2 phosphorylation are probably through inhibition of the N-methyl d-aspartate-mediated calcium influx, which subsequently reduce the hyperglycemia-exaggerated cerebral damage.     

肢体缺血/再灌注后氧自由基与Bax蛋白、细胞凋亡的关系

目的　阐明氧自由基与Bax蛋白、细胞凋亡在大鼠肢体缺血 /再灌注不同时相中的变化规律及相互关系。方法　采用大鼠股动脉夹闭模型 ,阻断股动脉血流 5h后再灌注 ,设立缺血组、再灌注组 ,再灌注组设立 1,6 ,12 ,2 4h 4个检测时相 ,应用硫代巴比妥酸法测定肌肉组织中脂质过氧化产物丙二醛 (MDA)水平 ,应用免疫组化方法测定Bax蛋白表达的变化 ,应用原位末端标记法及电镜方法观察细胞凋亡现象。结果　随着再灌注时间的延长 ,MDA水平、Bax蛋白表达强度、细胞凋亡指数 (AI)进行性升高 ,且三者呈显著正相关。结论　氧自由基与细胞凋亡同时参与肢体再灌注损伤 ,氧自由基可能通过调节Bax蛋白表达促进细胞凋亡的发生。     

Energy deficiency,calcium overload or oxidative stress: Possible causes of irreversible ischemic myocardial injury

Summary After prolonged ischemia or hypoxia myocardial injury is not reversed but exacerbated by a resupply of the tissue with oxygen and substrates. The mechanism by which reversible ischemic or hypoxic myocardial injury becomes irreversible is not yet understood. It has been debated whether reperfusion injury merely uncovers pre-existing irreversible injury, or is indeed caused by the reperfusion/reoxygenation process. In recent years, three theories have been discussed that relate the onset of irreversibility either to: a critical energy loss; a critical accumulation of cellular calcium; or to the deleterious effects of free radical formation. In certain experimental models for each of these theories favourable results have been obtained. Current research suggests that absolute reversibility thresholds in energy depletion or calcium accumulation in the ischemic or hypoxic cell do not exist. A key role of free radical injury for reperfusion injury must also be questioned. There is, however, evidence that in tissue reversibility of ischemic cardiomyocyte injury is limited by conditions that make calcium-induced hypercontracture upon reoxygenation unavoidable. This occurs when, by hypercontracture, mutual mechanical disruption of the cells destroys the tissue. From isolated cardiomyocytes that are able to metabolically survive hypercontracture it has been observed that these metabolic conditions do not represent the last biological possibility to reverse injury.     

Microwave Spectroscopy of Myocardial Ischemia and Infarction. 2. Biophysical Reconstruction

The proposed dielectrical relaxation model of the myocardium in the microwave spectrum has been verified both on test solutions and on normal canine myocardium. Furthermore, the model was utilized to reconstruct the changes in tissue properties (including myocardial bulk resistance and water content) following myocardial acute ischemia and chronic infarction. It was shown that the reconstructed myocardial resistance and water content correlate dynamically with the process of the development of acute myocardial ischemic injury. In chronic cases the reconstructed resistance and water content of infarcted myocardium are significantly different from that of normal myocardium: the resistance is lower and water content is higher than in normal myocardium. © 2000 Biomedical Engineering Society. PAC00: 8764-t, 8719Xx     

Postextrasystolic potentiation does not distinguish ischaemic from stunned myocardium

Myocardial function is impaired by ischaemia, and it remains depressed during reperfusion following short periods of ischaemia (stunned myocardium). We tested whether ischaemic and reperfusion dysfunction, in particular the time course of its recovery, can be distinguished by postextrasystolic potentiation (PESP). In eight open-chest dogs, posterior systolic wall thickening (sonomicrometry) was reduced by graded occlusion of the left circumflex coronary artery (LCX) from 17.4±6.8% (SD) during control conditions to 10.7±1.3% (mild ischaemic dysfunction), 7.2±2.3% (moderate ischaemic dysfunction), 3.6±1.4% (severe ischaemic dysfunction), and -4.4±3.6% (complete coronary occlusion). Extrasystoles with constant prematurity and a fully compensated postextrasystolic interval were induced after at least 4 min steady-state ischaemia. After each ischaemic period full recovery of posterior systolic wall thickening was assured. During 8 h of reperfusion following a 15-min LCX occlusion, extrasystoles were induced when posterior systolic wall thickening was comparable to one degree of the preceding ischaemic dysfunction. The increases in posterior systolic wall thickening induced by PESP were 10.5±5.8% during control conditions, during ischaemia they were 11.5±3.5% (mild dysfunction), 12.3±4.6% (moderate dysfunction), 12.6±4.1% (severe dysfunction) and 10.4±4.4% (complete coronary occlusion), and during reperfusion they were 12.8±8.2% (severe dysfunction), 13.0±9.7% (moderate dysfunction) and 10.7±2.2% (mild dysfunction). These increments in systolic wall thickening as well as those in ejection thickening were not significantly different. PESP can thus not distinguish between ischaemic and reperfusion dysfunction nor between different degrees of myocardial dysfunction.This study was supported by the Deutsche Forschungsge-meinschaft (He 1320/3-2). cand. med. S. Schäfer was involved in some of these experiments and presented part of the data at the 56th Annual Meeting of the Deutsche Gesellschaft für Herz- und Kreislaufforschung in Mannheim (Z Kardiol 79 [Suppl 1]: 24,1990). Part of the data were also presented at the 11th Congress of the European Society of Cardiology in Nice (Eur Heart J 10 [Suppl]: 242, 1989) and at the 73rd Annual Meeting of the Federation of American Societies for Experimental Biology in New Orleans (FASEB J 3: A841, 1989)     

茶黄烷醇对离体缺血再灌注鼠心心律失常的作用

本研究旨在探讨茶黄烷醇(TF)对离体缺血再灌注鼠心心律失常的作用。结果表明,对照组缺血后再灌注初期心律失常发生率高达91.67%(11/12),显著高于TF组(P<0.005),TF组心律失常发生率仅为23.08%(3/13);对照组心律失常持续时间平均为27.91±6.94min,TF组平均为9.83±6.21min,两组比较差异显著(P<0.001)。上述结果表明TF具有显著的抗缺血再灌性心律失常作用。     

Membrane attack complex of complement and 20 kDa homologous restriction factor (CD59) in myocardial infarction

In order to investigate the mechanism of deposition of the complement membrane attack complex (MAC) in cardiomyocytes in areas of human myocardial infarction, the 20 kDA homologous restriction factor of complement (HRF20; CD59) and complement components (C1q, C3d and MAC) were analysed immunohistochemically using specific antibodies. Myocardial tissues obtained at autopsy from nine patients who died of acute myocardial infarction were fixed in acetone and embedded in paraffin. The ages of the infarcts ranged from about 3.5 h to 12 days. In cases of myocardial infarction of 20 h or less, MAC deposition was shown in the infarcted cardiomyocytes without loss of HRF20. Where the duration was 4 days or more, the cardiomyocytes with MAC deposition in the infarcted areas also showed complete loss of HRF20. Outside the infarcts, HRF20 in the cardiomyocytes was well preserved without MAC deposition. The present study suggests that the initial MAC deposition in dead cardiomyocytes can occur as a result of degradation of plasma-membrane by a mechanism independent of complement-mediated injury to the membrane. Loss of HRF20 from dead cardiomyocytes may not be the initial cause of MAC deposition, but may accelerate the deposition process of MAC in later stages of infarction.     

Differential effects of scopolamine on neuronal survival in ischemia and glutamate neurotoxicity: relationships to the excessive vulnerability of the dorsoseptal hippocampus

The neurodegeneration in the CA1 subfield of hippocampus exhibited a dorsal-ventral gradient of susceptibility in global ischemia (82% dorsoseptally and only 16% ventrotemporally). Scopolamine (SCOP) did not improve the neuronal damage caused by the global ischemic challenge in rats and did not reduce the infarct area after the focal MCA-occlusion in mice. No differences were observed between saline and SCOP-treated animals in the physiologic parameters, except for a slight increase in rectal temperature. In contrast, treatment of hippocampal cultures with increasing concentrations of SCOP (1 nM to 1 mM) under glutamate incubation had a beneficial effect on neuronal viability. These data show that (1) there is substantial gradient of vulnerability of the hippocampus from dorsal to ventral in global ischemia and (2) that interactions between the NMDA, muscarinic receptors and their corresponding neurotransmitter inputs to hippocampal neurons are evident in vitro and may play a crucial role in neuronal neurodegeneration. However, the mechanisms underlying the high vulnerability of dorsal hippocampus still remain enigmatic.     

Localisation of myocardial ischaemia from the magnetocardiogram using current density reconstruction method: computer simulation study

A computer simulation study is performed to investigate the method of current density reconstruction to localise myocardial ischaemia. A computer model of the entire human heart is used to simulate the excitation and repolarisation process in eight topographically different cases of myocardial ischaemia. The associated magnetocardiogram is calculated at 37 positions of the KRENIKON^* biomagnetic measurement equipment. The method of current density reconstruction is applied at the S-point (the last discemible deviation from the ST-segment at the end of the QRS-complex) of the MCG to find characteristics of the myocardial ischaemia simulated by the model. The results show that it is possible to determine the location of the ischaemia. The current density distribution may be interpreted physiologically in terms of the so-called ‘injury current’. This indicates that magnetocardiography might be a suitable method for noninvasive ischaemia diagnosis, and further investigations of the current density reconstruction method for the injury current should be performed on patients with ischaemic heart disease.