Droxicainide对冠脉阻塞后心室纤颤及梗塞面积方面的有利作用

本工作观察了droxicainide对实验性心肌缺血和再灌注家兔模型的作用。家兔随机分为盐水对照组(n=18)或droxicainide治疗组(n=11)。在对照组,冠脉结扎后心室纤颤的发生率为14/18(77.7%),其中9只死亡;治疗组虽有8只动物(72.7%)出现心室纤颤,但全部自行恢复正常节律,无死亡情况发生(P<0.02)。此外,droxicainide治疗组的梗塞心肌面积为危险区的45.6±8.0%,而对照组则为60.9±7.4%(P<0.01)。在droxicainide治疗组未见任何不利的影响。这一实验表明,droxicainide可能在治疗缺血性心脏病方面具有一定的临床价值。     

Time course of infarct growth toward the endocardium after coronary occlusion.

Transmembrane potentials and ultrastructure of subendocardial Purkinje and ventricular muscle fibers, isolated 1, 3, 5, 6, 14, and 24 h after coronary occlusion were investigated. Action potentials were recorded from progressively fewer layers of muscle cells as the age of the infarct increased. At 14 h little viable muscle remained. The decrease in the number of electrophysiologically viable muscle fibers correlated with structural evidence that the infarct moved with time toward the endocardial surface until only viable Purkinje fibers remained. Purkinje and surviving ventricular muscle fibers demonstrated a progressive decrease in resting potential, action potential amplitude, and Vmax and a progressive increase in action potential duration. Spontaneous diastolic depolarizations were found in Purkinje fibers only in 24-h infarcts and occasionally in cells deep to the endocardial surface, which may have been muscle cells. We hypothesize that during the first 24 h after coronary occlusion arrhythmias originate near the interface of infarcted and ischemic myocardium. As this interface moves toward the endocardium, this site of origin of arrhythmias moves with it until the Purkinje network is reached.     

Delayed treatment of Na+/H+ exchange inhibitor SM-20220 reduces infarct size in both transient and permanent middle cerebral artery occlusion in rats

SM-20220 (N-(aminoiminomethyl)-1-methyl-1H-indole-2-carboxamide methanesulfonate) is a Na+/H+ exchanger (NHE) inhibitor which has been shown to attenuate cerebral edema in the rat transient focal ischemia model. However, to date, the effect of SM-20220 on cerebral infarction has not been examined. The present experiments were designed to investigate these effects, using both transient and permanent middle cerebral artery (MCA) occlusion models in rats. A dose of 1 mg/kg given intravenously 30 min after the onset of transient MCA occlusion reduced the infarcted area. In the permanent MCA occlusion model, SM-20220 reduced the infarcted area when treatment was delayed for 5, 30 or 60 min after the onset of ischemia. The present results show that NHE has a crucial role in the pathogenesis of ischemic brain damage. This NHE inhibitor may be useful for treating stroke because of its effectiveness with both forms of ischemia and because of its postischemic administration.     

Time-dependent changes of decorin in the infarct zone after experimentally induced myocardial infarction in rats: comparison with biglycan

Decorin, a small dermatan sulphate proteoglycan, has been postulated to interact with other components of the extracellular matrix. We examined time-dependent changes of decorin in the infarct zone after experimentally induced myocardial infarction in rats by Northern blotting, in situ hybridization, and immunohistochemistry. The expression of decorin mRNA was compared to that of biglycan mRNA. Northern blotting demonstrated that the decorin mRNA expression was not increased in the infarct zone on day 2, while increased biglycan mRNA was observed at that time (average 3.1-fold increase). Decorin mRNA expression was increased on day 7, and reached a peak (average 2.2-fold increase) around day 14. Biglycan mRNA expression also reached a peak level around day 14 (average 13.3-fold increase). In situ hybridization revealed that mRNA signals for decorin did not appear in the infarct zone on day 2, while biglycan mRNA signals were observed. Decorin mRNA signals were observed in spindle-shaped mesenchymal cells in the infarct peripheral zone on day 7. The decorin mRNA signals appeared later than those of biglycan. Immunopositive staining for decorin was observed in the infarct zone on day 7. The present results demonstrated a time-dependent increase in decorin mRNA expression in mesenchymal cells in the infarct zone in rats. Decorin mRNA appeared later and was increased to a lower extent in the infarct zone than biglycan mRNA.     

Effect of prolonged cortical stimulation differs with size of infarct after sensorimotor cortical lesions in rats

Motor deficit improvement is limited in rats with a large sensorimotor cortex infarct, even with cortical stimulation during rehabilitation. However, we find prolonged stimulation that differs with the size of cortical lesion to be effective. Two weeks of prolonged epidural electrical stimulation and rehabilitative training were delivered to rats whose cortex had been subjected to photothrombotic infarct after training in a single-pellet reaching task. Continuous stimulation greatly improved recovery in animals with large infarcts (6 mm diameter), while intermittent stimulation was more effective in animals with small (4 mm) lesions. Thus, prolonged cortical stimulation is a strategy to enhance motor recovery in photothrombotic infarct model rats. However, pattern and duration of stimulation requires modification depending on the extent of infarct.     

L-丝氨酸对永久性大脑中动脉栓塞大鼠的神经保护作用

目的: 研究L-丝氨酸对大鼠永久性脑梗死的神经保护作用、治疗剂量及有效治疗时间窗,并探讨相关作用机制。方法: 制作大鼠永久性大脑中动脉栓塞(pMCAO)模型,腹腔注射L-丝氨酸,通过神经行为学评分、脑梗死体积测定和尼氏染色法,观察L-丝氨酸的治疗剂量效应(56 mg/kg、168 mg/kg和504 mg/kg治疗组)和治疗时间窗(1 h、3 h、6 h、12 h和24 h治疗组);并测定丝氨酸消旋酶抑制剂对L-丝氨酸疗效的影响。利用激光多普勒血流监测仪观察缺血区血供及L-丝氨酸对缺血区局部脑血流量的影响。结果: 与pMCAO组相比,L-丝氨酸于pMCAO后3 h使用,168 mg/kg和504 mg/kg两个剂量都能较好地降低神经行为学评分,减少脑梗死体积,抑制海马CA1区神经细胞的丢失。在治疗时间窗的研究中,L-丝氨酸在pMCAO后6 h内治疗具有明显的神经保护作用,12 h及以后使用,神经保护作用不明显。丝氨酸消旋酶抑制剂不改变L-丝氨酸的疗效。脑缺血30 min时注射L-丝氨酸可明显增加缺血区局部脑血流量,并且这一作用不受甘氨酸受体阻断剂士的宁的影响。结论: L-丝氨酸对永久性脑梗死具有神经保护作用,其机制可能部分与增加缺血区皮质的血供有关。     

Filament size influences temperature changes and brain damage following middle cerebral artery occlusion in rats

Postischemic spontaneous hyperthermia as a complication of occlusion of the middle cerebral artery with an intraluminal filament has been observed by some authors, but many other reports do not discuss this factor. The possible reasons why some of the authors have not seen severe hyperthermia in their experiments include differences in surgical technique, the strain of animals, the type of the anesthesia, and the occluder filament. The aim of this study was to examine the changes in the core temperature of rats using different types of filaments. The middle cerebral artery was occluded for 2 h with three different types of filaments. The changes in the temperature were continuously monitored during occlusion and for the next 4 h. Groups with uncontrolled hyperthermia and with controlled normal core temperature were used. In addition, the necrotic and penumbral areas were measured 4 and 48 h after the ischemia in both groups. Spontaneous postischemic hyperthermia was detected using all types of filaments. A close correlation was found between the size of the occluder filament and the time-course and degree of hyperthermia. Moreover, the size of the filament correlated well with the size of the infarct at both 4 and 48 h after the occlusion. We suggest that filament size is a major contributor to the degree of hyperthermia and the development of brain damage in the middle cerebral artery occlusion model. Our results call attention to the need to standardize the methods used to screen for therapeutic agents for stroke.     

Acute geometric changes of the mitral annulus after coronary occlusion: a real-time 3D echocardiographic study

We performed real-time 3D echocardiography in sixteen sheep to compare acute geometric changes in the mitral annulus after left anterior descending coronary artery (LAD, n=8) ligation and those after left circumflex coronary artery (LCX, n=8) ligation. The mitral regurgitation (MR) was quantified by regurgitant volume (RV) using the proximal isovelocity surface area method. The mitral annulus was reconstructed through the hinge points of the annulus traced on 9 rotational apical planes (angle increment=20 degrees). Mitral annular area (MAA) and the ratio of antero-posterior (AP) to commissure-commissure (CC) dimension of the annulus were calculated. Non-planar angle (NPA) representing non-planarity of the annulus was measured. After LCX occlusion, there were significant increases of the MAA during both early and late systole (p<0.01) with significant MR (RV: 30+/-14 mL), while there was neither a significant increase of MAA, nor a significant MR (RV: 4+/-5 mL) after LAD occlusion. AP/CC ratio (p<0.01) and NPA (p<0.01) also significantly increased after LCX occlusion during both early and late systole. The mitral annulus was significantly enlarged in the antero-posterior direction with significant decrease of non-planarity compared to LAD occlusion immediately after LCX occlusion.     

Lidocaine attenuates apoptosis in the ischemic penumbra and reduces infarct size after transient focal cerebral ischemia in rats

Lidocaine is a local anesthetic and antiarrhythmic agent. Although clinical and experimental studies have shown that an antiarrhythmic dose of lidocaine can protect the brain from ischemic damage, the underlying mechanisms are unknown. In the present study, we examined whether lidocaine inhibits neuronal apoptosis in the penumbra in a rat model of transient focal cerebral ischemia. Male Wistar rats underwent a 90-min temporary occlusion of middle cerebral artery. Lidocaine was given as an i.v. bolus (1.5 mg/kg) followed by an i.v. infusion (2 mg/kg/h) for 180 min, starting 30 min before ischemia. Rats were killed and brain samples were collected at 4 and 24 h after ischemia. Apoptotic changes were evaluated by immunohistochemistry for cytochrome c release and caspase-3 activation and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) for DNA fragmentation. Cytochrome c release and caspase-3 activation were detected at 4 and 24 h after ischemia and DNA fragmentation was detected at 24 h. Double-labeling with NeuN, a neuronal marker, demonstrated that cytochrome c, caspase-3, and TUNEL were confined to neurons. Lidocaine reduced cytochrome c release and caspase-3 activation in the penumbra at 4 h and diminished DNA fragmentation in the penumbra at 24 h. Lidocaine treatment improved early electrophysiological recovery and reduced the size of the cortical infarct at 24 h, but had no significant effect on cerebral blood flow in either the penumbra or core during ischemia. These findings suggest that lidocaine attenuates apoptosis in the penumbra after transient focal cerebral ischemia. The infarct-reducing effects of lidocaine may be due, in part, to the inhibition of apoptotic cell death in the penumbra.     

Early morphologic changes in cat heart muscle cells after acute coronary artery occlusion.

The left descending coronary artery (LAD) was occluded in 16 open-chest cats for 10, 20, 40, or 60 minutes (four cats in each group). In addition, four sham-operated cats served as controls. Specimens for electron microscopy were obtained from the normal and ischemic zones, guided by in vivo injection of fluorescein, and verified by blood flow measurements with microspheres. The ultrastructure of 2,400 heart muscle cells and nuclei was studied. Fractional volumes of main cell components, mitochondrial surface density, and mitochondrial surface: volume ratio were calculated in 480 micrographs. After 10 minutes of ischemia we observed signs of sarcolemmal fragility, mitochondrial swelling, and lipid droplet accumulation. After 20 minutes of ischemia sarcolemmal fragmentation, chromatin clumping or margination and a maximal cytoplasmic edema were evident. The fractional volume of mitochondria was equally increased in ischemic zones of all groups. In both normal and ischemic zones there was a tendency toward smaller fractional volumes of lipid droplets during ischemia. In the normal zone there was mild cytoplasmic edema and slight mitochondrial swelling 10 minutes after occlusion as compared with the sham group. The present study demonstrates that a large proportion of cardiac myocytes undergoes severe damage within 20 minutes of coronary occlusion.     

Relationship between enzymatically estimated infarct size and short- and long-term survival after acute myocardial infarction

In 585 patients with acute myocardial infarction (AMI) and no previous MI the maximal activity of serum heat-stable lactate dehydrogenase (LD) (EC 1.1.1.27) activity was related to 1-year and 2-year mortality rates. All patients participated in a double-blind trial with metoprolol during the first three months after an AMI. Thereafter both groups were treated in a similar way. A strong relationship was found between LD maximum activity and the in-hospital prognosis (p less than 0.001), the 1-year survival rate (p less than 0.001) and the 2-year survival rate (p less than 0.001). When the patients who were alive after primary hospitalization were analyzed as a separate group, the relationship between LD maximum activity and 1-year and 2-year survival rates remained (p less than 0.001). In a subsample of 171 patients the maximal activity of creatine kinase (CK) (EC 2.7.3.2) and CK subunit B did not correlate either with in-hospital, 1-year or 2-year survival rates. We conclude that, when a sufficiently large number of patients are investigated, there is a strong relationship between serum enzyme maximum activity and short- and long-term survival.     

Nylon filament coated with paraffin for intraluminal permanent middle cerebral artery occlusion in rats

A variety of intraluminal nylon filament has been used in rat middle cerebral artery occlusion (MCAO) models. However the lesion extent and its reproducibility vary among laboratories. The properties of nylon filament play a part of reasons for these variations. In the present study, we used paraffin-coated nylon filament for rat MCAO model, tested the effects and advanced improvement for making the rat MCAO. Forty male Sprague-Dawley (SD) rats were randomized into two groups, MCAO with traditional uncoated nylon filament (uMCAO) and MCAO with paraffin-coated nylon filament (cMCAO), three rats as normal group and sham group respectively. Assessment included mortality rates, model success rates, neurological deficit evaluation, and infarct volume. The study showed two rats died in uMCAO group, no rat died in cMCAO group within the 12 h. The model success rate of uMCAO was 100%, while the uMCAO group was 55% (n = 20, two died within 12 h, seven rats were excluded as the brain slices showed no TTC staining due to subarachanoid hemorrhage). Neurological evaluation demonstrated group cMCAO had more worse neurological outcomes than group uMCAO, and the difference was statistically signification (p < 0.05). TTC staining cMCAO group had significantly larger infarct volumes than uMCAO group, and also showed statistically significant difference (p < 0.05). The result demonstrated that the paraffin-coated nylon filament intraluminal occlusion provide better occlusion of middle cerebral artery than the uncoated nylon filament, improve the consistent of model, and raise the success rate to reduce the number of experimental animals. These positive results are much encouraging and interesting.     

Nylon filament coated with paraffin for intraluminal permanent middle cerebral artery occlusion in rats

Decreased dopamine (DA) release in the hippocampus may be caused by dysfunctional mastication, although the mechanisms involved remain unclear. The present study examined the effects of soft- and hard-food diets on oxidative stress in the brain, and the relationship between these effects and hippocampal DA levels. The present study showed that DA release in the hippocampus was decreased in rats fed a soft-food diet. Electron spin resonance studies using the nitroxyl spin probe 3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl directly demonstrated a high level of oxidative stress in the rat brain due to soft-food diet feeding. In addition, we confirmed that DA directly react with reactive oxygen species such as hydroxyl radical and superoxide. These observations suggest that soft-food diet feeding enhances oxidative stress, which leads to oxidation and a decrease in the release of DA in the hippocampus of rats.     

心肌梗死早期体温改变与梗死面积的相关性

冠心病对人类健康的威胁日益严重,梗死程度评估为心肌梗死患者治疗方案的选择和预后判断提供了重要的依据.正电子发射显像(PET)被认为是识别存活心肌的"金标准",但PET需要特殊设备、费用昂贵,不易连续检测且尚难普及.因此寻求一种简单、低廉可连续监测心肌梗死程度的方法成为临床急需解决的问题.