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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent data suggest that brain damage in ischemia, hypoglycemia, and several other brain diseases is caused by excitotoxic mechanisms which are triggered by presynaptic release of glutamate and related excitatory amino acids, and which involve an abnormal postsynaptic influx of calcium into cells containing a high density of glutamate receptors. This contention is supported by results demonstrating reduction of infarct size in focal ischemia due to middle cerebral artery (MCA) occlusion, and amelioration of neuronal necrosis in hypoglycemic coma, by antagonist which block the NMDA type of glutamate receptor. These results underscore the pathogenetic role of calcium influx into energy-compromised cells since the NMDA receptor-linked ion channel has a high conductance to calcium. The issue has been clouded by the inability of NMDA antagonists to ameliorate brain damage due to cardiac arrest, or to forebrain ischemia in rats and gerbils. In these conditions, however, an AMPA receptor blocker (NBQX) has been found efficacious. These results demonstrate that the pathophysiology of ischemic lesions is different in the cardiac arrest type of ischemia and in lesions due to MCA occlusion, and demand an explanation of the differences in therapeutic response. Tentatively, the cardiac arrest type of ischemia is so dense that multiple calcium conductances are activated in the energy-deprived tissue, explaining why any drug which acts on only one of them (such as an NMDA antagonist) cannot prevent cellular calcium overload. Furthermore the ultimate brain damage, which is often conspicuously delayed, may be secondary to upregulation of synaptic efficacy, causing increased calcium cycling and calcium-related damage. In this situation, an AMPA receptor blocker may be efficacious because it blocks "fast" excitation and Na+ influx, an "upstream" event which causes "downstream" calcium influx via multiple pathways. In the perifocal ("penumbra") zone of a stroke lesion, the situation is different since depolarisation is initially moderate and/or intermittent. Furthermore, since ATP is still produced (albeit at a reduced rate) the problem is one of a disturbed pump/leak relationship. Then, blockade of a major calcium-carrying channel by NMDA receptor blockers, or of the trigger to depolarisation by an AMPA receptor antagonist, may improve the pump/leak relationship and carry cells in the penumbra over a critical period.
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PMID:Neurocytotoxicity: pharmacological implications. 168 4

Marked hyperemia accompanies reperfusion after ischemia in the brain, and may account for the propensity of cerebral hemorrhage to follow embolic stroke or carotid endarterectomy, and for the morbidity that follows head injury or the ligation of large arteriovenous malformations. To evaluate the contribution of trigeminal sensory fibers to the hyperemic response, CBF was determined in 12 symmetrical brain regions, using microspheres with up to five different isotopic labels, in four groups of cats. Measurements were made at 15-min intervals for up to 2 h of reperfusion after global cerebral ischemia induced by four-vessel occlusion combined with systemic hypotension of either 10- or 20-min duration. In normal animals, hyperemia in cortical gray matter 30 min after reperfusion was significantly greater after 20 min (n = 10) than after 10 min (n = 7) of ischemia (312 ml/100 g/min versus 245 ml/100 g/min; p less than 0.01). CBF returned to preischemic levels approximately 45 min after reperfusion and was reduced to approximately 65% of basal CBF for the remaining 75 min. In cats subjected to chronic trigeminal ganglionectomy (n = 15), postocclusive hyperemia in cortical gray matter was attenuated by up to 48% on the denervated side (249 versus 150 ml/100 g/min; p less than 0.01) after 10 min of ischemia. This effect was maximal in the middle cerebral artery (MCA) territory, and was confined to regions known to receive a trigeminal innervation. In these animals, substance P (SP) levels in the MCA were reduced by 64% (p less than 0.01), and the density of nerve fibers containing calcitonin gene-related peptide (but not vasoactive intestinal polypeptide or neuropeptide Y) was decreased markedly on the lesioned side. Topical application of capsaicin (100 nM; 50 microliters) to the middle or posterior temporal branch of the MCA 10-14 days before ischemia decreased SP levels by 36%. Postocclusive hyperemia in cortical gray matter was attenuated throughout the ipsilateral hemisphere by up to 58%, but the cerebral vascular response to hypercapnia (PaCO2 = 60 mm Hg) was unimpaired. The duration of hyperemia and the severity of the delayed hypoperfusion were not influenced by trigeminalectomy, capsaicin application, or the intravenous administration of ATP. These data demonstrate the importance of neurogenic mechanisms in the development of postischemic hyperperfusion, and suggest the potential utility of strategies aimed at blocking axon reflex-like mechanisms to reduce severe cortical hyperemia.
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PMID:Chronic trigeminal ganglionectomy or topical capsaicin application to pial vessels attenuates postocclusive cortical hyperemia but does not influence postischemic hypoperfusion. 170 54

The objective of the present study was to assess changes in cellular energy metabolism in focal and perifocal areas of a stroke lesion and to explore how these changes are modulated by preischemic hyperglycemia. A model for reversible occlusion of the middle cerebral artery (MCA) in rats was used to study changes in energy metabolism. Following MCA occlusion for 5, 15, or 30 min in normoglycemic rats, the tissue was frozen in situ, and samples from the lateral caudoputamen and from two neocortical areas were collected for metabolite analyses, together with a control sample from the contralateral, nonischemic hemisphere. Two other groups, subjected to 30 min of MCA occlusion, were made hyperglycemic by acute glucose infusion or by prior injection of streptozotocin. Enzymatic techniques were used for measurements of phosphocreatine, creatine, ATP, ADP, AMP, glycogen, glucose, pyruvate, and lactate. The neocortex of the contralateral, nonischemic hemisphere had labile metabolites that were similar to those measured in control animals. Ipsilateral neocortex bordering the focus, and thus constituting the "penumbra," showed mild to moderate ischemic changes. In the "focus" (lateral caudoputamen plus the overlying neocortex), deterioration of energy state was rapid and relatively extensive (ATP content 20-40% of control). After 5 min of occlusion, no further deterioration of metabolic parameters was observed. Substrate levels were markedly reduced, and lactate content rose to approximately 10 mM kg-1.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Focal and perifocal changes in tissue energy state during middle cerebral artery occlusion in normo- and hyperglycemic rats. 172 40

Binding of iodine-125-labeled thrombin to fibrin clots from two siblings with juvenile stroke was 30% of normal, and abnormally high amounts of the radioligand (not adsorbed by fibrin) were found in the supernatant. In concordance with this finding, supernatants from the patients' fibrin clots caused abnormal enhancement of platelet aggregation, ATP secretion, and binding of 125I-fibrinogen to platelets exposed to subthreshold concentrations of ADP or epinephrine. Hirudin suppressed the enhancing effect of the patients' supernatants, and substitution of gamma-thrombin for alpha-thrombin led to normalization of platelet responses. Under some experimental conditions, degradation of the patients' fibrinogen by plasmin was impaired. However, the euglobulin lysis time, the rate of fibrin degradation by plasmin, and the lysis of the patients' plasma clots by human melanoma tissue-type plasminogen activator were normal. Patients' plasmas, as well as purified fibrinogen, showed a prolonged thrombin time (partially corrected by 10 mM CaCl2) and an impaired release of fibrinopeptide A in response to thrombin. However, the release in response to reptilase was normal, and the reptilase, ancrod, and thrombin coagulase times were within control (normal) values. In addition, the patients' fibrinogen showed normal polymerization of preformed fibrin monomers, normal sialic acid content, and normal binding to ADP or epinephrine-stimulated platelets. Our studies support the concept that thrombin and platelets play an important role in the occurrence of stroke in these patients and suggest a direction to be followed to identify the mechanism(s) contributing to thrombosis in subjects with abnormal fibrinopeptide release.
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PMID:A role for platelets and thrombin in the juvenile stroke of two siblings with defective thrombin-adsorbing capacity of fibrin(ogen). 182 31

In vivo 31P-nuclear magnetic resonance (31P-NMR) spectroscopy and ion-selective electrode measurements were undertaken to determine if administration of acute doses of alcohol (ALC, 0.2-6.6 g/kg), and lethal doses of barbiturate anesthesia, exert any influence on: (1) brain cellular bioenergetics, intracellular free Mg ([Mg2+]i) and intracellular pH (pHi), and (2) serum levels of ionized Mg (IMg2+), ionized calcium (ICa2+) and K+. Approximately 20-30 min after intraperitoneal administration of ALC to anesthetized rats, brain phosphocreatine (PCr)/ATP and PCr/inorganic phosphate (P(i)) ratios dropped from 2.5 to 1.7 and from 6.6 to 2.2, respectively, P(i) rose 20-200% (depending upon ALC dose), and free ADP and creatine rose significantly. ALC induced rapid decreases in the cytosolic phosphorylation potential (CPP) and free energy of ATP hydrolysis (-delta G/delta E). Following ALC administration, brain [Mg2+]i dropped rapidly (within 4-30 min) and significantly; the greater the dose of ALC, the greater the loss in brain [Mg2+]. Correlations were found between [Mg2+]i, PCr/ATP, CPP and delta G/delta E after ALC but not in control brains. Rats that exhibited ALC-induced strokes and death (unlike barbiturate death) exhibited huge elevations in [Mg2+]i. Although ALC administration does not alter brain pHi at least (up to 70 min), ALC- and barbiturate-induced death produces rapid brain intracellular acidosis. Concomitant with ALC-induced alterations in [Mg2+]i and brain cellular bioenergetics, we noted that ALC administration results in rapid elevations in serum IMg2+ and K+ but not ICa2+. These results suggest that ALC administration and heavy or binge-drinking of ALC (1) can result in rapid alterations in brain bioenergetics, [Mg2+]i and pHi, and (2) result in rapid elevations in serum IMg2+ and K+ in rats. In addition, ALC- and barbiturate-induced deaths do not appear to produce identical alterations in brain bioenergetics and [Mg2+]i, and lastly binge or heavy drinking of ALC may result in stroke-like events and sudden death via rapid alterations in brain cellular bioenergetics.
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PMID:Alcohol intoxication results in rapid loss in free magnesium in brain and disturbances in brain bioenergetics: relation to cerebrovasospasm, alcohol-induced strokes, and barbiturate anesthesia-induced deaths. 184 45

The cellular bioenergetic responses of isolated perfused working rat hearts to alterations in hemodynamic function caused by acute exposure to elevated levels of extracellular magnesium ions ([Mg2+]o) were examined using 31P nuclear magnetic resonance (31P NMR) spectroscopy. Results showed that in hearts working against 90 cm H2O afterload, an increase in [Mg2+]o from 1.2 to 4.8 mM reduced the heart rate by 35%, while coronary flow was increased by 38%. Unexpectedly, despite the pronounced bradycardia, the rate-pressure product was reduced only slightly (from 2.36 x 10(4) to 2.08 x 10(4) mm Hg/min) due to a significant increase (36%) in systolic pressure. In addition, cardiac output actually increased by 23%, owing to a > 100% increase in stroke volume, indicating that the performance of the heart was improved and suggesting that the efficiency of the heart was improved as well. In a separate series of experiments, 31P NMR measurements performed on hearts perfused in the Langendorff mode revealed that elevated levels of [Mg2+]o increase phosphocreatine (PCr) levels by 23% (from 9.2 to 11.3 mM), while Pi levels declined by a corresponding amount. Perfusion of hearts in the working mode with elevated [Mg2+]o was also observed to increase PCr levels from 6.3 to 9.0 mM, while ATP levels declined by 17%. Measurement of the chemical shift difference between Pi and PCr and that between the alpha and beta phosphate resonances of ATP were used to determine intracellular pH and the cytosolic levels of free Mg2+ ([Mg2+]i), respectively. These results showed that acute exposure of hearts, perfused in either the working or Langendorff mode, to increased levels of [Mg2+]o increased intracellular pH by 0.12-0.13 units, while free Mg2+ nearly doubled to a level of 1.1-1.2 mM. The latter observation may suggest that acute variations in the level of [Mg2+]o can influence a multitude of cellular processes requiring Mg2+ as an essential cofactor. Using the above data and assuming equilibrium of the creatine kinase reaction, the levels of ADP, cytosolic phosphorylation potential ([ATP]/[ADP][Pi]) and free energy change from ATP hydrolysis (-delta G/delta E) were also calculated. Results obtained illustrate that in the presence of elevated [Mg2+]o, ADP levels declined by 33-48%, the cytosolic phosphorylation potential increased from 41 to 112 mM-1 and -delta G/delta E increased from 56.7 to 59.3 kJ/mol. These changes are not completely accountable by the known bradycardia and vasodilatory effects of elevated [Mg2+]o and strongly argue for a direct action of [Mg2+]o on the myocyte as well.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Influence of Mg2+ on cardiac performance, intracellular free Mg2+ and pH in perfused hearts as assessed with 31P nuclear magnetic resonance spectroscopy. 184 66

Muscle contraction is generally thought to be driven by tilting of the 19-nm-long myosin head, part of the thick filament, while attached to actin, part of the thin filament. This motion would produce about 12 nm of filament sliding. Recent estimates of the sliding distance per ATP molecule hydrolysed by actomyosin in vitro vary widely from 8 nm to greater than or equal to 200 nm. The latter value is incompatible with a power stroke incorporating a single tilting motion of the head. We have measured the isotonic sliding distance per ATP molecule hydrolysed during the interaction between myosin and actin in skinned muscle fibres. We directly estimated the proportion of simultaneously attached actomyosin complexes and their ATP use. We report here that at low loads the interaction distance is at least 40 nm. This distance corresponds to the length of the power stroke plus the filament sliding while actomyosin crossbridges bear negative drag forces. If the power stroke is 12 nm, then our results indicate the drag distance to be at least 28 nm. Our results could also be explained by multiple power strokes per ATP molecule hydrolysed.
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PMID:Sliding distance between actin and myosin filaments per ATP molecule hydrolysed in skinned muscle fibres. 185 12

Vascular responses to ATP were studied in aortic rings isolated from stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY). Low concentrations of ATP (10 nM to 10 microM) caused relaxation and high concentrations (0.1 mM to 10 mM) caused contraction. Both of these responses were accentuated by factors released from the endothelium. The endothelium-derived relaxing factor (EDRF) was blocked by NG-monomethyl-L-arginine (L-NMMA). This is the first time that it has been reported that ATP causes the release of an endothelium-derived contracting factor (EDCF). Its release was diminished but not completely blocked by cyclooxygenase inhibitors. Assays of muscle bath prostanoid composition indicated that ATP stimulation caused the release of prostaglandins I2 and E2 and thromboxane A2 from intact aortic rings. Evidence is presented that neither endothelin nor superoxide anion contributed to the EDCF. No difference was observed between WKY and SHRSP with regard to either the endothelial contributions to the response, or the direct action on vascular smooth muscle of ATP. High concentrations of ATP achieved intravascularly in hypoxia may cause vasospasm by release of endothelial prostanoids.
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PMID:Contraction and relaxation of rat aorta in response to ATP. 185 26

The effect of chronic antiplatelet treatment on PAF--induced platelet aggregation, ATP--release, and cytoplasmic ionized calcium was studied in 20 acute ischemic stroke patients. Chronic antiplatelet treatment failed to suppress these PAF--induced platelet responses. We speculate that selective PAF antagonists may be useful in suppressing PAF--induced platelet activation, and thereby possibly improve the treatment of stroke.
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PMID:[Effect of chronic antiplatelet treatment on platelet activating factor-induced platelet activity in stroke]. 186 62

The present study was designed to elucidate pathophysiological changes in the brain energy metabolism after cerebral ischemia. Cerebral ischemia was induced in rats by administering microspheres into the right carotid canal, and the time course of changes in cerebral energy metabolism was examined up to the 7th day after the operation. Approximately 50% of the operated rats revealed typical symptoms of stroke. In the right hemisphere, cerebral ATP and creatine phosphate of the rat on the 1st to 7th day were greatly reduced by the microsphere-induced cerebral embolism (maximally 52 and 61%, respectively), whereas the tissue lactate level was increased on the 1st, 3rd and 5th day after the embolism (maximally 125%), suggesting an induction of microsphere-induced cerebral ischemia. These changes in the tissue metabolites were accompanied by a decrease in the mitochondrial oxidative phosphorylation measured in the presence of succinate. A similar trend in the changes of biochemical markers was observed in the left hemisphere, but to a lesser degree or to an insignificant degree. The pathophysiological alterations in behavior and cerebral metabolism of microsphere-injected rats tended to return toward the normal levels on the 7th day after the operation. The results provided information on a useful model for therapeutic studies of anti-ischemic agents in the brain.
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PMID:Time course of changes in brain energy metabolism of the rat after microsphere-induced cerebral embolism. 206 39


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