Loss of cerebral regulation during cardiac output variations in focal cerebral ischemia.

Focal cerebral ischemia was induced in anesthetized macaque monkeys by unilateral middle cerebral artery occlusion. The effect of blood volume expansion by a colloid agent and subsequent exsanguination to baseline cardiac output (CO) on local cerebral blood flow (CBF) was measured by the hydrogen clearance technique in both ischemic and nonischemic brain regions. Cardiac output was increased to maximum levels (159% +/- 92%, mean +/- standard error of the mean) by blood volume expansion with the colloid agent hetastarch, and was then reduced a similar amount (166% +/- 82%) by exsanguination during the ischemic period. Local CBF in ischemic brain regions varied directly with CO, with a correlation coefficient of 0.89 (% change CBF/% change CO), while CBF in nonischemic brain was not affected by upward or downward manipulations of CO. The difference in these responses between ischemic and nonischemic brain was highly significant (p less than 0.001). The results of this study show a profound loss of regulatory control in ischemic brain in response to alterations in CO, thereby suggesting that blood volume variations may cause significant changes in the intensity of ischemia. It is proposed that CO monitoring and manipulation may be vital for optimum care of patients with acute cerebral ischemia.     

Therapeutics for focal cerebral ischemia

A review of the therapeutic modalities available for the treatment of focal cerebral ischemia is presented. The theoretical aspects and present practical applications of each treatment are discussed. The possibilities for future research and for the implementation of new modalities are indicated.     

Lipid peroxidation in focal cerebral ischemia

To verify whether lipid peroxidation is associated with focal cerebral ischemia, a unilateral middle cerebral artery occlusion was carried out in rats. The concentrations of various endogenous antioxidants in the ischemic center were measured, including alpha-tocopherol and ubiquinones as lipid-soluble antioxidants and ascorbate as a water-soluble antioxidant. At 30 minutes after ischemia, alpha-tocopherol decreased to 79% of baseline, reduced ubiquinone-9 to 73%, ubiquinone-10 to 66%, and reduced ascorbate to 76%. Six hours after ischemia, alpha-tocopherol decreased to 63% and reached a plateau, whereas reduced ubiquinones and reduced ascorbate declined further to 16% and 10%, respectively, 12 hours after ischemia and then reached plateau levels. These results suggest functional and durational differences between antioxidants and lipid peroxidation in this ischemic model. Although the reciprocal increase in oxidized ubiquinones during ischemia was not observed, that of oxidized ascorbate was noted. The complementary antioxidant system between cytoplasmic and membranous components, the combination alpha-tocopherol/ascorbate, was estimated from the calculated consumption ratio of these antioxidants on the basis that the loss of these reduced antioxidants is due to neutralization of free radicals. This system is suggested to play an important role in the early ischemic period. Urate also increased during ischemia. The possible involvement of the xanthine-xanthine oxidase system in initiating free radical reactions in cerebral ischemia is also discussed.     

Reperfusionable focal cerebral ischemia in rats

Reperfusionable focal cerebral ischemia by embolization to the middle cerebral artery with nylon thread adhered to sponge was studied in rats. It was divided into 2 groups: permanent embolization and embolization for 3 hours. Neurological symptoms, degree of brain swelling and size of cerebral infarction of these animals were observed. The laboratory statistics was no difference between the two groups. But it was found in pathological specimens that infarction area were limited in the basal-ganglion with perivascular hemorrhage in 3 rats after reperfusion. Establishment of the model, symptoms of rats, results of laboratory and it's clinical significances were discussed.     

Protection of focal cerebral ischemia by alkalinization of systemic pH

OBJECT: It has been demonstrated in many studies that intracellular brain acidosis during cerebral ischemia is a significant factor in perpetuating the cycle of cellular dysfunction leading to neuronal injury. The purpose of this study was to determine whether preischemic administration of alkalotic agents could reduce neuronal injury after focal cerebral ischemia. METHODS: Fifteen fasted rabbits under 1.0% halothane anesthesia were randomized into three groups: Group 1 rabbits were ischemic controls (n = 5) that underwent 4 hours of focal cerebral ischemia. Groups 2 and 3 rabbits underwent a paradigm similar to that of Group 1, except that they were pretreated with either sodium bicarbonate or Carbicarb at similar buffering capacities. Intracellular brain pH (pH(i)), regional cortical blood flow (rCBF), and intrinsic reduced nicotinamide adenine dinucleotide (NADH) fluorescence were measured with in vivo fluorescence imaging. At the end of each experiment, infarct volume expressed as a percentage of hemispheric volume was measured by triphenyltetrazolium chloride staining. RESULTS: Preischemic alkalinization did not alter brain pH(i), rCBF, or NADH fluorescence. After 4 hours of ischemia, brain pH(i), rCBF, NADH fluorescence, and infarct volume measured 6.40 +/- 0.09 (mean +/- standard error), 11 +/- 2 ml/100 g/min, 165 +/- 8% of baseline control, and 37 +/- 3% in ischemic controls, respectively. In Group 2 animals treated with sodium bicarbonate, brain pH(i), rCBF, NADH fluorescence, and infarct volume improved significantly (P < 0.05, analysis of variance) to 6.74 +/- 0.08, 24 +/- 6 ml/100 g/min, 137 +/- 6% of baseline control, and 22 +/- 4%, respectively. Group 3 Carbicarb animals demonstrated improvements in brain pH(i), rCBF, and NADH fluorescence, with a significant reduction in infarct volume. CONCLUSION: These findings suggest that pretreatment with alkalinizing agents may be a useful intervention to provide intraoperative cerebral protection from ischemic injury.     

Brain tissue pressure in focal cerebral ischemia

Twenty-three anesthetized cats underwent permanent middle cerebral artery occlusion in a study of the relationships of regional cerebral blood flow, ventricular fluid pressure, brain tissue pressure, and ischemic edema formation. A pressure gradient of 8 mm Hg developed between ischemic tissue and normally perfused tissue during a 4-hour observation period after occlusion. Brain water accumulated as tissue pressure rose, while blood flow in the same area fell. The data suggest, but do not prove, that ischemic brain edema causes tissue pressure to rise focally, and that blood flow to the ischemic zone is compromised further by the resultant hydrostatic pressure gradient.     

Inflammation in stroke and focal cerebral ischemia

BACKGROUND: A growing number of recent investigations have established a critical role for leukocytes in propagating tissue damage after ischemia and reperfusion in stroke. Experimental data obtained from animal models of middle cerebral artery occlusion implicate inflammatory cell adhesion molecules, chemokines, and cytokines in the pathogenesis of this ischemic damage. METHODS: Data from recent animal and human studies were reviewed to demonstrate that inflammatory events occurring at the blood-endothelium interface of the cerebral capillaries underlie the resultant ischemic tissue damage. RESULTS: After arterial occlusion, the up-regulated expression of cytokines including IL-1, and IL-6 act upon the vascular endothelium to increase the expression of intercellular adhesion molecule-1, P-selectin, and E-selectin, which promote leukocyte adherence and accumulation. Integrins then serve to structurally modify the basal lamina and extracellular matrix. These inflammatory signals then promote leukocyte transmigration across the endothelium and mediate inflammatory cascades leading to further cerebral infarction. CONCLUSIONS: Inflammatory interactions that occur at the blood-endothelium interface, involving cytokines, adhesion molecules, chemokines and leukocytes, are critical to the pathogenesis of tissue damage in cerebral infarction. Exploring these pathophysiological mechanisms underlying ischemic tissue damage may direct rational drug design in the therapeutic treatment of stroke.     

Hydroxyethyl-starch in transient experimental focal cerebral ischemia

Summary In a model of focal cerebral ischaemia in the cat (transorbital occlusion of the middle cerebral artery for 60 minutes, thereafter 6 hours reperfusion by clip removal), hydroxyethyl-starch (HAES) (ELOHES; Leopold Pharma GmbH, Graz, Austria) was administered intravenously before and during the ischaemic episode as a 6% or as a 10% solution in a randomised manner (6 animals each group).The size of the developing cerebral infarct was not significantly different when comparing the 6% and the 10% group with the controls (SALINE). Collateral circulation to the infarct border (pial arteries on the suprasylvian gyrus) was also not significantly different between the two groups, except for the first hour of reperfusion, where vessels of the 6% group were wider than vessels of the 10% group. At the infarct border (ectosylvian gyrus) small resistance vessels were significantly more dilated in the 6% than in the 10% group both during the occlusion period and during the reperfusion episode after removal of the clip.Pial arteries dilated less in both HAES-groups than in the controls.It can be assumed, that HAES-incuded decrease of plasma viscosity led to an elevation of blood flow velocity and blood flow quantity (CBF). But the latter might be counteracted by autoregulation of CBF, i.e. vasoconstriction. Thus, a possible positive effect of HAES might in part be counteracted by autoregulation, which explaines that no significant therapeutic effect could be achieved.     

局灶性脑缺血后海马的电生理学观察

目的 观察将在体记录扩散性抑制的电生理学方法 应用于局灶性脑缺血后远隔缺血区(海马)的电生理学改变.方法 采用局部给予3 mol/L高浓度氯化钾溶液,光化学血栓形成局灶性脑缺血模型和大脑中动脉栓塞局灶性脑缺血模型诱导扩散性抑制;抑制组预先30 min腹腔注射MK-801(0.2 mg/100 g);将记录电极加以改良置入海马记录细胞外直流电位变化.结果 诱导组记录到幅度约10～30 mV,时程大于1～2 min的扩散性抑制波,抑制组未记录到SD波.并观察到大脑中动脉栓塞脑缺血模型诱导的海马扩散性抑制波.结论 SD波可能参与MCAO模型中海马远隔效应的发生.     

Polyamine and prostaglandin markers in focal cerebral ischemia

This study examines the pathophysiology of stroke secondary to focal cerebral ischemia. The interaction of arachidonic acid metabolites and polyamines, a class of ubiquitous ornithine-derived molecules with important membrane effects on edema, Ca++-dependent endocytosis, platelet function, and prostaglandin (PG) formation, are correlated with regional changes in H2 clearance, cerebral blood flow (rCBF), ischemic edema, and somatosensory evoked responses (SSERs) after middle cerebral artery (MCA) occlusion. Thirty cats were studied up to 3 hours before and 6 hours after right MCA occlusion. Four areas of brain showing different levels of perfusion after MCA occlusion were sampled for tissue levels of PGs: 6-keto-PGF1 alpha, PGE2, and as well as thromboxane B2 (TXB2), ornithine decarboxylase activity (ODC) (a measure of polyamine activity) and gravimetric determination of cerebral edema. After right MCA occlusion, right hemisphere SSER amplitude decreased and interpeak latency increased markedly. rCBF was distributed into zones of dense, partial, and no ischemia ranging from 12.6 to 59.4 ml/100 g/minute. Ischemic edema was distributed inversely to rCBF and was increased in areas of dense ischemia (85.2 +/- 0.5%) and ischemia (82.7 +/- 0.7%), but not in partially ischemic or control areas. 6-Keto-PGF1 alpha (1257.3 pg/mg), PGE2 (1628.5 pg/mg), and TXB2 (1572.8 pg/mg) were all significantly (P less than 0.05) increased in areas of partial ischemia that had not yet developed edema. ODC levels were significantly elevated (3812 pmole/g/hour, P less than 0.05) and increased with time in areas of slightly denser ischemia that showed an intermediate increase in edema, but not the presence of infarction. This is the first demonstration that ODC, the rate-limiting enzyme for polyamine synthesis, is stimulated by cerebral ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of naloxone on focal cerebral ischemia in cats

The effect of naloxone, opiate antagonist, was investigated on systemic arterial blood pressure(BP), cerebral blood flow (CBF), and cerebral oxygen consumption in the cat brain following occlusion of the middle cerebral artery(MCA). A total of 21 adult cats was studied under the anesthesia of alpha-chloralose (50 mg/kg). The left MCA was exposed and coagulated using transorbital approach under a operation microscope. Naloxone of 5 mg/kg was administrated intravenously within 30 minutes after MCA occlusion in early therapy group and 2.5 hours after the occlusion in delayed therapy group. Isotonic saline was administrated in the control group. The basal value of CBF in the intact animals was 54.0 +/- 5.9 (+/- SEM) ml/100g/min. Significant increases in mean BP of 13%, CBF of 12%, and CMRO2 of 16% were noted in the intact animals after naloxone administration. The CBF in MCA territory reduced to 24% after MCA occlusion and 85% in contralateral hemisphere. MCA occlusion had no significant effect on either mean BP or the difference in oxygen concentration between arterial and superior sagittal sinus blood. Naloxone increased these reduced CBF and mean BP significantly, but increase in oxygen consumption was not significant. There was no difference between early therapy group and delayed therapy group in pathological study. The effect of naloxone was temporary. Therapy of repeated or continuous naloxone administration appears to be effective during temporary focal cerebral ischemia.     

氨基胍对局灶性脑缺血诱导大鼠脑神经元凋亡的影响

目的观察选择性诱导型一氧化氮合酶抑制剂氨基胍(AG)对局灶性脑缺血诱导大鼠脑神经元凋亡的影响,探讨AG对脑缺血大鼠脑神经元的保护作用及其机制。方法健康雄性SD大鼠54只,体重250-300 g,随机分为3组:假手术组(SH组)、缺血组(IS组)、AG治疗组(AG组),每组18只。每组按给药时机分为3个亚组:缺血2 h组、缺血6 h组、缺血12 h组,每亚组6只。IS、AG组采用插线法制备大鼠大脑中动脉阻断模型。AG组每次腹腔注射AG 100 mg/kg,每日2次,连续3 d。IS 组给予等量的生理盐水。治疗后大鼠断头取脑,采用流式细胞仪测定脑组织神经元凋亡率、Bcl-2蛋白、Bax蛋白表达及Bcl-2蛋白与Bax蛋白比值(Bcl-2/Bax)。结果与SH组比较,IS、AG组各亚组神经元凋亡率及Bax蛋白表达升高,AG组各亚组Bcl-2蛋白表达升高,IS、AG组各亚组Bcl-2/Bax降低(P <0.01);与IS组比较,AG组各亚组神经元凋亡率降低,AG组各亚组Bcl-2蛋白表达及Bcl-2/Bax升高,AG组Bax蛋白表达降低(P<0.05或0.01)。结论AG通过增加Bcl-2蛋白表达,降低Bax蛋白表达,调节Bcl-2/Bax平衡,对脑缺血大鼠脑神经元产生一定程度的保护作用。     

L-精氨酸对局灶性脑缺血大鼠神经元凋亡的影响

目的 评价L-精氨酸(L-arg)对局灶性脑缺血大鼠神经元凋亡的影响.方法 健康雄性SD大鼠56只,体重250～300 g,随机分为7组(n=8):假手术组(SH组)、脑缺血2 h组(Is1组)、脑缺血2 h L-arg治疗组(L-arg1组)、脑缺血6 h组(IS2组)、脑缺血6 h L-arg治疗组(L-arg2组)、脑缺血12h组(IS3组)及脑缺血12 h L-arg治疗组(L-arg3组).采用线栓法制备大鼠大脑中动脉阻塞模型.各L-arg治疗组分别于脑缺血后腹腔注射L-精氨酸500 mg/kg,2次/d,治疗3 d;IS组给予等容量生理盐水.治疗3 d后取脑,测定缺血区域神经元凋亡率、Caspase-3蛋白、Bcl-2蛋白和Bax蛋白的表达水平.结果 与SH组比较,IS1组、IS2组和IS3组神经元凋亡率升高,Caspase-3蛋白和Bax蛋白表达上调,Bcl-2/Bax蛋白比值降低(P＜0.01);与IS1组和IS2组比较,L-arg1组和L-arg2组神经元凋亡率降低,Caspase-3蛋白和Bax蛋白表达下调,Bcl-2蛋白表达上调,Bcl-2/Bax蛋白比值升高(P＜0.01).IS3组与L-arg3组上述指标差异无统计学意义(P＞0.05).结论 L-arg可减少脑缺血早期大鼠神经元凋亡,具有一定的治疗作用,其机制可能与下调Caspase-3蛋白表达、调节Bcl-2/Bax蛋白平衡有关.     

谷氨酸增强脑缺血-再灌注后肠的炎性反应

目的研究谷氨酸对脑缺血性损害引起的肠炎性反应的影响。方法成年雄性SD大鼠接受15 min双侧颈总动脉夹闭,造成局灶性脑缺血损伤,缺血同时腹腔内注射大剂量谷氨酸单钠。在缺血-再灌注后6 h分别收集血浆和小肠组织,用酶联免疫吸附法(ELISA)测定血浆和肠组织中的肿瘤坏死因子α(TNF-α)含量;用[32磷]-ATP标记核因子-κB(NFκ-B)寡核苷酸探针,聚丙烯酰胺凝胶电泳成像组织中的NF-κB,计算机软件半定量分析NF-κB活性变化。实验当中,连续监测血液动力学参数改变并记录。结果脑的短暂性缺血可引起肠TNFα-含量的轻度增加,而谷氨酸单钠可引起肠中的TNF-α含量显著增加;缺血联合应用谷氨酸单钠可使肠中的TNF-α含量较单独应用谷氨酸单钠时显著减低;NF-κB活性检测结果与TNF-α含量变化相一致。在整个实验过程中,各组平均动脉压和心率基本保持在基线水平。结论大量谷氨酸可增加肠的炎症反应;谷氨酸增加肠的炎性反应主要通过激活NF-κB信号转导途径而实现的。     

Treatment of acute focal cerebral ischemia and recirculation with d-propranolol

The purpose of the investigation was to evaluate the effects of d-propranolol upon temporary cerebral ischemia followed by a period of reperfusion, that is, a situation analogous to major cerebral artery embolization. Twenty adult cats, lightly anesthesized with nitrous oxide, underwent 4 hours of right middle cerebral artery (MCA) occlusion and 2 hours of recirculation. Ten cats were untreated and 10 cats received d-propranolol, the weak beta-blocking isomer of racemic (d,l) propranolol. The d-propranolol was infused directly into the right carotid artery at doses of 2 mg/kg, given as a bolus immediately before MCA occlusion, and 0.33 mg/kg/hour, given continuously for 6 hours beginning immediately after MCA occlusion. Systemic arterial blood pressure was similar in both groups, but heart rate was transiently reduced in the treated group immediately after the bolus injection of d-propranolol and MCA occlusion. Regional cerebral blood flow (rCBF), measured by the xenon-133 clearance technique, was not significantly different in the ischemic, right hemisphere. Electroencephalographic (EEG) activity changes in the ischemic, right hemisphere were similar in both groups, but there was significant deterioration of EEG activity in the left, nonischemic hemisphere of untreated cats after MCA reopening. Swelling of the ischemic, right hemispheres was similar in both groups and more severe than in previous studies wherein there was no recirculation phase. Carbon perfusion and blood-brain barrier changes were also similar. The results of the study failed to show a protective effect despite theoretical beneficial actions of d-propranolol. Also, the study demonstrated that d-propranolol does not have a detrimental effect upon rCBF in acute focal cerebral ischemia.     

Thromboxane synthetase inhibition in acute focal cerebral ischemia in cats

The purpose of this investigation was to study the effects of a selective thromboxane A2 (TXA2) synthetase inhibitor (TSI) upon the evolution of cerebral infarction in the cat. Adult cats, lightly anesthetized with nitrous oxide, underwent right middle cerebral artery (MCA) occlusion for 4 hours followed by a 2-hour period of reperfusion before sacrifice. Ten cats received 3 mg/kg TSI intravenously immediately before, and 10 cats received 3 mg/kg TSI intravenously immediately after MCA occlusion. Ten cats were used as controls receiving no treatment. The bleeding time was determined at baseline and at the end of each experiment. Electroencephalographic (EEG) recordings were obtained before and after MCA clipping and MCA release, and at hourly intervals thereafter. Regional cerebral blood flow (rCBF) was measured using the xenon-133 (133Xe) clearance technique before and after MCA occlusion, after MCA reopening, and before terminating each experiment. Thirty minutes before each cat was sacrificed, Evans blue dye and sodium fluorescein were given intravenously. The animals were then perfused with colloidal carbon and the brains removed and evaluated for midline shift. Evans blue dye and sodium fluorescein extravasation, carbon staining, and infarct size. The bleeding time, arterial blood pressure, rCBF changes, brain swelling, and vital dye extravasation were not statistically different between the three treatment groups. The EEG changes, carbon staining, and infarct size differences between the three groups also failed to reach statistical significance, but there was a suggestion that these parameters were adversely affected in the cats pretreated with TSI. Ten additional cats undergoing MCA occlusion and reperfusion were used for pharmacological studies. Five of them received 3 mg/kg TSI intravenously immediately after MCA occlusion, and serial drug and thromboxane B2 (TXB2) levels (a stable metabolite of TXA2) were determined. Another five cats were not treated and serial TXB2 levels were obtained. Production of TXA2 was inhibited by 95% in cats receiving TSI. In conclusion, thromboxane synthetase inhibition failed to modify favorably the evolution of cerebral infarction. When TSI was given before MCA occlusion, cerebral infarction tended to be more extensive.     

Hypervolemic hemodilution in experimental focal cerebral ischemia. Elevation of cardiac output, regional cortical blood flow, and ICP after intravascular volume expansion with low molecular weight dextran

Cerebrovascular and cardiac alterations evoked by intravascular volume expansion with low molecular weight dextran (LMD, molecular weight 40,000), an advocated adjunct in the clinical prevention or therapy of acute stroke and cerebral vasospasm, were studied in splenectomized dogs. Clipping of the right distal internal carotid artery and the proximal middle cerebral artery (MCA) in eight dogs decreased regional cortical blood flow (rCoBF) by 58% without changing cardiac output (CO), and caused 10% +/- 5% (SE) hemispheric infarction. Ten other dogs underwent similar cerebral arterial occlusion and were infused twice with LMD within 2 hours; each infusion equaled 20% of the respective dog's total blood volume. Both CO and rCoBF in the territory of the occluded MCA increased significantly by 119% +/- 13% and 42% +/- 6%, respectively. following the two LMD infusions. Although the mean arterial blood pressure was unaltered, the hematocrit decreased significantly and the intracranial pressure (ICP) increased significantly. The mean hemispheric infarction in these 10 treated dogs was 4% +/- 2%. Another nine dogs underwent arterial manipulation without clipping. Two hemodiluting LMD infusions, similar to those in the 10 dogs, significantly elevated CO and ICP but not rCoBF. These data suggest that hypervolemic hemodilution with LMD effectively elevates collateral perfusion to ischemic regions of brain distal to occluded MCA segments and concomitantly raises the CO and ICP.