Showing papers in "Journal of Cerebral Blood Flow and Metabolism in 1981"
TL;DR: In this article, it was shown that the clinically most important conditions leading to brain cell death are those associated with cerebrovascul ar dise ase, particularly stroke, and with head trauma.
Abstract: All cells in living organisms have a limited life span, and when the time set by their biological clocks has run out, they will die , their highly orga nized macromolec ular structure will disintegrate, and the low-molec ul ar degrad ation products be come part of the disorder of the surroundings . In thermodynamic terms, this series of events consti tutes what has been c alled the entropic doom. We know little about those molec ul ar mechanisms that limit the life span of cells in the absence of dise ase. For the clinician, therefore, the important task is to prevent or tre at dise ases that jeopardize the proper functioning and viability of cells whose biologic al clocks have not yet run out . Measures instituted to prevent brain cell death have a special importance . This i s partly due t o the fact that w e equate human life with the functioning of the brain. However, this importance also resides in the v ulnerability of brain cells to conditions that allow cells of most other tissue to survive , and to continue or res ume their activitie s . The clinically most important conditions leading to brain cell death are those associated with cere brovascul ar dise ase, particularly stroke, and with head trauma. We will begin, though, by rec alling the traditional view of the occ urrence and loc alization of neuronal damage in four conditions that lead to more disseminated alterations, e specially since they have been considered to c ause nerve cell injury of a
1,640 citations
TL;DR: The ability to produce a consistent focal ischaemic lesion in the rodent brain provides a technical approach that is sufficiently reproducible to enable investigation of the pathophysiology of ischaemia using recently developed autoradiographic and neurochemical methods.
Abstract: Summary: A procedure for occluding the stem of the proximal middle cerebral artery of the rat is described. The operation is performed under anaesthesia through a small subtemporal craniectomy. After occlusion, 3 animals were perfused with carbon black and 8 with a FAM fixative (40% formaldehyde, glacial acetic acid, and methanol). The findings were compared with sham-operated animals. Carbon black studies demonstrated an area of impaired perfusion corresponding to the territory of the occluded artery in each animal. Neuropathological studies invariably showed that there was ischaemic brain damage in the cortex and basal ganglia. The frontal cortex was involved in every animal, as was the lateral part of the neostriatum; the sensorimotor and auditory cortex were involved in most animals, whereas the occipital cortex and medial striatum were involved only infrequently. The damage produced by ischaemia could be readily distinguished from the small local lesion seen at the surgical site in sham-operated animals. The ability to produce a consistent focal ischaemic lesion in the rodent brain provides a technical approach that is sufficiently reproducible to enable investigation of the pathophysiology of ischaemia using recently developed autoradiographic and neurochemical methods.
1,426 citations
TL;DR: It is concluded that a high degree of tissue lactic acidosis during brain ischemia impairs postischemic recovery and that different degrees of tissue nacreous acidosis may explain why severe incomplete ischemIA, in certain experimental models, is more deleterious than complete brain is chemia.
Abstract: This study explores the influence of severe lactic acidosis in the ischemic rat brain on postischemic recovery of the tissue energy state and neurophysiological parameters. Severe incomplete brain ischemia (cerebral blood flow below 5% of normal) was induced by bilateral carotid artery clamping combined with hypovolemic hypotension. We varied the production of lactate in the tissue by manipulating the blood glucose concentrations. A 30-min period of incomplete ischemia induced in food-deprived animals caused lactate to accumulate to 15-16 mumol g-1 in cortical tissue. Upon recirculation these animals showed: (1) a considerable recovery of the cortical energy state as evaluated from the tissue concentrations of phosphocreatine, ATP, ADP, and AMP; and (2) return of spontaneous electrocortical activity as well as of somatosensory evoked response (SER). In contrast, administration of glucose to food-deprived animals prior to ischemia caused an increase in tissue lactate concentration to about 35 mumol g-1. These animals did not recover energy balance in the tissue and neurophysiological functions did not return. In other experiments the production of lactate during 30 min of complete compression ischemia was increased from about 12 mumol g-1 (normoglycemic animals) to 20-30 mumol g-1 by preischemic hyperglycemia and, in separate animals, combined hypercapnia. The recovery of the cortical energy state upon recirculation was significantly poorer in hyperglycemic animals. It is concluded that a high degree of tissue lactic acidosis during brain ischemia impairs postischemic recovery and that different degrees of tissue lactic acidosis may explain why severe incomplete ischemia, in certain experimental models, is more deleterious than complete brain ischemia.
582 citations
TL;DR: Sokoloff provided a review of his lab's deoxyglucose work so far: the theory and properties of the [14C] deoxyGlucose and its derivative [18F] fluorodeoxy glucose methods, and their applications to many physiological, pharmacological, and pathological conditions.
Abstract: Sokoloff provided a review of his lab's deoxyglucose work so far: the theory and properties of the [14C] deoxyglucose
and its derivative [18F] fluorodeoxyglucose methods, and their applications to many physiological, pharmacological, and pathological
conditions.
545 citations
TL;DR: It is concluded that excessive tissue lactic acidosis during brain ischemia exaggerates structural alterations and leads to irreversible cellular damage.
Abstract: Summary: The influence of severe tissue lactic acidosis during incomplete brain ischemia (30 min) on cortex morphology was studied in fasted rats. Production of lactate in the ischemic tissue was varied by preischemic infusions (i.v.) of either a saline or a glucose solution. The brains were fixed by perfusion with glutaraldehyde at 0, 5, or 90 min of recirculation. In saline-infused animals (tissue lactate about 15 µmol g-1), changes observed at 0 and 5 min of recirculation were strikingly discrete: slight condensation of nuclear chromatin, mild to moderate mitochondrial swelling, and only slight astrocyte edema. These changes had virtually disappeared after 90 min recirculation and, at this time, only discrete ribosomal changes were observed. In contrast, glucose-infused rats (tissue lactate about 35 µmol g-1) showed severe changes: marked clumping of nuclear chromatin and cell sap in all cells was already evident at 0 and 5 min recirculation, while mitochondrial swelling was mild to moderate. Although tissue fixation was inadequate at 90 min, the ultrastructural appearance indicated extensive damage. It is concluded that excessive tissue lactic acidosis during brain ischemia exaggerates structural alterations and leads to irreversible cellular damage. A tentative explanation is offered for the paucity (<0.2%) of condensed neurons with grossly swollen mitochondria, previously considered a hallmark of ischemic cell injury.
398 citations
TL;DR: It was shown that at a blood flow of approximately 10 ml 100 g−1 min−1, there is a threshold below which ion homeostasis is disturbed, and this is associated with a dramatic rise in Ke and fall in Cae, which is related to local cerebral blood flow.
Abstract: Changes in extracellular ion activities were measured during partial ischaemia of the cerebral cortex of primates anaesthetized with alpha-chloralose. Triple-barrelled, double-ion-sensitive microelectrodes were used to measure the extracellular potassium (Kc) and calcium (Cac) activity at the same point simultaneously. The ion changes were related to local cerebral blood flow, and it was shown that at a blood flow of approximately 10 ml 100 g-1 min-1, there is a threshold below which ion homeostasis is disturbed. This is associated with a dramatic rise in Ke and fall in Cae. Cae falls from a normal value of 1.31 +/- 0.1 mM to approximately 0.28 mM in densely ischaemic tissue. In ischaemia, Ke reaches 13.4 +/- 3.8 mM before Cae begins to fall. The fall in Cae, although related to reduced blood flow, is closely associated with and follows the rise in Ke. The change in Cae is probably due to an increase in membrane permeability, as a result of either depolarisation or a critical lowering of cellular energy reserves.
358 citations
TL;DR: It is suggested that this finding and the reductions in blood flow outside the territory of the middle cerebral artery are reflections of alterations in neuronal function and metabolic activity secondary to the ischaemic lesion.
Abstract: Local cerebral blood flow has been measured by quantitative autoradiography, employing (14C)iodoantipyrine as tracer, in rats killed half an hour after occlusion of the middle cerebral artery. The results were compared with pattern of local cerebral blood flow (CBF) in sham-operated rats and with neuropathological findings. In every animal there was a profound reduction (to 13% of control levels)in blood flow in the neocortex previously by the occluded artery. The level of blood flow in the areas in which ischaemic brain damage occurred was 0.24 +/- 0.03 ml g-1 min-1 (mean +/- SEM). this level of CBF is considerably greater than that reported following a similar surgical procedure in cats and primates. Moderate reductions in blood flow were also seen outside the territory of the occluded artery and in parts of the opposite hemisphere. Absolute increases in blood flow (hyperaemia) were seen only in the substantia nigra and globus pallidus ipsilateral to the occlusion. It is of the middle cerebral artery are reflections of alterations in neuronal function and metabolic activity secondary to the ischaemic lesion.
322 citations
228 citations
TL;DR: Prostaglandins are biosyn the sized fro m arachidonic acid and dihomo-y linolenic acid, both of which are derived from the essential unsaturated long-chain dietary fatty acids, and are the predominant substrate for prostaglandin synthesis in the brain.
Abstract: What normally provides "tone" in the cerebral circulation? What adjusts cerebral blood flow to ce rebral metabolism? Why invoke arachidonic acid and its metabolites? The derivatives of arachidonic acid form an ex traordinary and bewildering array of compounds of widely differing propertie s. Von Euler ( 1 93 6) created the term "prostaglandin" to christen the depressor, smooth-muscle-stimulating acidic lipid that he and Goldblatt had demonstrated in human seminal plasma. Bergstrom began to determine the structure of this group of compounds in 1 947 with publication in the early 1 960s (for review , see Bergstrom et aI. , 1 968). Prostaglandins are biosyn the sized fro m arachidonic acid and dihomo-y linolenic acid , both of which are derived from the essential unsaturated long-chain dietary fatty acids. Arachidonic acid is the predominant substrate for prostaglandin synthesis in the brain. Following the isolation and description of the effects of the pri mary and relatively stable prostaglandins (PGF2a , PGE1 , PGE2, PGD2, etc.) came the discovery that prostaglandin synthe s i s was inhibited by the nonsteroidal antiinflammatory age nts such as indomethacin and aspirin (Vane , 1 97 1). Certain dis crepancies became apparent in the period 1 970-76 between the effects of prostaglandin synthesis inhi bition and the effects of the known endogenous prostaglandins. Then , in rapid succession , came the description of the short-lived derivatives of arachi-
177 citations
TL;DR: The evidence suggests that nimodipine has no effect on cerebral metabolism but increases CBF, particularly after disruption of the blood-brain barrier.
Abstract: The effect of the calcium antagonist nimodipine was tested in anaesthetised primates A rapid intravenous injection of 3 or 10 micrograms kg-1 produced a transient rise in end-tidal PCO2 and a fall in arterial blood pressure, but 10 min after the injection there was no significant change in CBF A continuous intravenous infusion of 2 micrograms kg-1 min-1 caused a modest fall in mean arterial blood pressure and an increase in cerebral blood flow (CBF), which gradually increased to 27% above control after 50 min infusion There was no significant change in CMRO2 A continuous intracarotid infusion of 067 micrograms kg-1 min-1 caused an increase in CBF of between 46 and 57% This was further increased to 87% above control after disruption of the blood-brain barrier with hyperosmolar urea Thirty minutes after the urea, the CBF returned to 43% above control Twenty minutes after the infusion of nimodipine had been stopped, the CBF had returned to control values EEG studies in this group showed no obvious increase in electrocortical activity This evidence suggests that nimodipine has no effect on cerebral metabolism but increases CBF, particularly after disruption of the blood-brain barrier
162 citations
TL;DR: Accumulations introduced in the calculated local cerebral glucose metabolism by inappropriate rate constants appear to be more significant than those caused by any potential change in the lumped constant in ischemia.
Abstract: Summary: The model for quantifying local cerebral glucose metabolic rates originally developed by Sokoloff et al. and modified by Phelps, Huang and co-workers was applied to humans with cerebral ischemia (i.e., stroke). Rate constants for fluorodeoxyglucose were measured in ischemic and nonischemic regions with positron computed tomography. Using measured rate constants for ischemia, the model generates more accurate estimates of local cerebral glucose metabolism as compared to the use of rate constants from normal young adults, because the local metabolic rate is significantly underestimated, and temporal instability of the model is observed when normal values are applied to ischemic regions. A method was also developed to test the stability of the local lumped constant. The estimates of the lumped constant showed no or only small variations between ischemic and nonischemic types. Thus, errors introduced in the calculated local cerebral glucose metabolism by inappropriate rate constants appear to be more significant than those caused by any potential change in the lumped constant in ischemia.
TL;DR: These alterations obviously suggest that astrocytes react to graded hypoxia with an increased metabolic activity and that alterations occur in their ionic and water contents.
Abstract: It is well established that gliosis may result from virtually any severe damage to brain tissue, al though it is not known to what extent the gliotic cells correspond to their normal counterparts, The characteristics of such cells is not the topic of the present review, Recently, much more subtle mor phological alterations in astrocytes have, however, been observed in the rat brain after graded hypoxia that is not severe enough to lead to an infarction but does lead to neuronal necrosis (Pulsinelli and Brierley, 1979), The alterations of astrocytic mor phology include an almost instantaneous, transient dilatation of astrocytic cytoplasm (Babiak and Petito, 1980) followed by a more slowly developing increase in mitochondrial density, apparent in the perivascular end-feet 40 min after the hypoxic insult and in the perikarya a few hours later (Petito, 1981). These alterations obviously suggest that astrocytes react to graded hypoxia with an increased metabolic activity and that alterations occur in their ionic and water contents. Pronounced changes are known to occur in the intracellular ionic contents of whole brain during and after ischemia (Hossmann et aI. , 1977; Hossmann, 1980). Thus, 1 h of complete ischemia causes an increase of total brain osmolality from about 300 to about 350 mOsm/liter, with no appar ent accumulation of the major ions, glucose, lactate, or adenine nuc1eotides (Hossmann, 1980). The ex tracellular sodium concentration in the brain de-
TL;DR: From pharmacological and biochemical experiments, it is suggested that the sympathomimetic reduction in the rate of CSF formation is the result of a combined β-receptormediated inhibition of the secretion from the plexus epithelium and a reduced blood flow in the choroid plexUS tissue resulting from stimulation of the vascular α-receptionors.
Abstract: The choroid plexuses of all ventricles receive a well-developed adrenergic and cholinergic innervation reaching both the secretory epithelium and the vascular smooth muscle cells. Also peptidergic nerves, containing vasoactive intestinal polypeptide, are present but primarily associated only with the vascular bed. A sympathetic inhibitory effect on the plexus epithelium has been indicated in determinations of carbonic anhydrase activity and by studies of various aspects of active transport in isolated plexus tissue. Pharmacological analysis in vitro has shown the choroidal arteries to possess both vasoconstrictory alpha-adrenergic and vasodilatory beta-adrenergic receptors. Electrical stimulation of the sympathetic nerves, which originate in the superior cervical ganglia, induces as much as 30% reduction in the net rate of cerebrospinal fluid (CSF) production, while sympathectomy results in a pronounced increase, about 30% above control, in the CSF formation. There is strong reason to believe that the choroid plexus is under the influence of a considerable sympathetic inhibitory tone under steady-state conditions. From pharmacological and biochemical experiments it is suggested that the sympathomimetic reduction in the rate of CSF formation is the result of a combined beta-receptor-mediated inhibition of the secretion from the plexus epithelium and a reduced blood flow in the choroid plexus tissue resulting from stimulation of the vascular alpha-receptors. The choroid plexus probably also represents an important inactivation site and gate mechanism for sympathomimetic amines, as evidenced by considerable local activity of catechol-O-methyl transferase and monoamine oxidase, primarily type B. The CSF production rate is also reduced by cholinomimetic agents, suggesting the presence of muscarinic-type cholinergic receptors in the choroid plexus.
TL;DR: It is suggested that potassium, amines, and prostaglandin F2α activate isolated pial and mesenteric arteries by different calcium-dependent mechanisms and confirm the potent relaxant effects of nifedipine and nimodipine in these vessels.
Abstract: In isolated human pial arteries (diameter 0.4–0.5 mm), contractions were produced by potassium, noradrenaline, serotonin, and prostaglandin F2α. For comparison, experiments were also performed on human mesenteric arteries. Threshold concentration for potassium-induced contraction in pial arteries was about 10 mm; in mesenteric arteries it was 3–5 mm higher. In pial arteries the calcium antagonists nifedipine and nimodipine caused an almost complete relaxation of contractions induced by potassium at drug concentrations relaxing prostaglandin F2α-contracted vessels to only about 60%. Both nifedipine and nimodipine effectively inhibited contraction elicited by noradrenaline and serotonin in pial arteries. Nifedipine had a higher potency for relaxing cerebral than mesenteric arteries contracted by potassium (p < 0.001). No such difference was demonstrated for nimodipine. In pial arteries pretreated in a calcium-free medium for 30 min, potassium depolarisation elicited contractions reaching a maximum amplitude...
TL;DR: In cat and guinea-pig, blood vessels in the choroid plexus were surrounded by few SP nerve fibres; also spinal cord blood vessels of cat contained few such fibres.
Abstract: Nerve fibres containing immunoreactive substance P (SP) were demonstrated in the wall of cerebral blood vessels of several mammalian species. Pial arteries of cat and guinea-pig were richly supplied with SP nerve fibres, while those of rat, rabbit, pig, and man had a moderate number. SP fibres were more numerous in pial vessels belonging to the rostral parts of the circle of Willis as compared to more caudally located blood vessels. In cat and guinea-pig, blood vessels in the choroid plexus were surrounded by few SP nerve fibres; also spinal cord blood vessels of cat contained few such fibres.
TL;DR: It is conceivable that in ischemic cerebrovascular disease, the vasomotor adjustment was impaired in such a manner that the relations among Ht, CBF, and oxygen delivery were different from those in healthy subjects.
Abstract: The contribution of hematocrit (Ht) changes on cerebral blood flow (CBF) and brain oxygenation in ischemic cerebrovascular disease is still controversial. In the present study, effects of Ht variations of CBF and oxygen delivery were investigated in patients with ischemic cerebrovascular disease. CBF was measured by the Xe-133 intracarotid injection method in 27 patients, whose diagnoses included completed stroke, reversible ischemic neurological deficit, and transient ischemic attack. Ht values in the patients ranged from 31 to 53%. There was a significant inverse correlation between CBF and Ht in these Ht ranges. Oxygen delivery, i.e., the product of arterial oxygen content and CBF, increased with Ht elevation and reached the maximum level in the Ht range of 40-45% and then declined. The CBF-Ht and oxygen transport-Ht relations observed in our study were similar to those in the glass-tube model studies by other workers rather than to those in intact animal experiments. From these results, it is conceivable that in ischemic cerebrovascular disease, the vasomotor adjustment was impaired in such a manner that the relations among Ht, CBF, and oxygen delivery were different from those in healthy subjects. Further, an "optimal hematocrit" for brain oxygenation was also discussed.
TL;DR: Computer simulations were used to evaluate the accuracy of the FDG method in cases where the tissue LCMRGlc deviates greatly from the normal values or the tissue changes during the experiment, and the results provide a better understanding of the accuracy.
Abstract: The fluorodeoxyglucose (FDG) method for the measurement of local cerebral metabolic rate of glucose (LCMRGlc) employs typical values of the FDG transport rate constants that have been obtained by kinetic measurements on an appropriate control group Discrepancies between the true values of the rate constants in tissue and the typical values used in the operational equation of the FDG method will introduce error in the estimate of LCMRGlc Computer simulations were used to evaluate the accuracy of the FDG method in cases where (1) the tissue LCMRGlc deviates greatly from the normal values (eg, stroke) or (2) the tissue LCMRGlc changes during the experiment (eg, epileptic seizure) The effects of the magnitude and duration of metabolic changes were studied The rsults indicate that if tissue LCMRGlc differs greatly from the normal value, the error in the estimated LCMRGlc at a scan time of 60 min is less than 20% of the difference between the true and normal values In the non-steady-state cases, the es
TL;DR: Evidence derived from the differential potency of binding displacement by the various β-adrenergic agonists and selective β1- and β2- adrenergic antagonists indicates that β-Adrenergic receptors of pig cerebral microvessels are mostly of theβ2-subtype.
Abstract: The presence of alpha- and beta-adrenergic and muscarinic cholinergic receptors in cerebral microvessels of the rat and pig was assessed by ligand binding techniques. The results demonstrate the presence of specific binding to alpha 2- and beta-adrenergic receptors but no appreciable specific binding to alpha 1-adrenergic or muscarinic cholinergic receptors. beta-Adrenergic receptors of pig cerebral microvessels are similar to those of the brain and other organs in their binding characteristics to the tritiated ligand and in their stereospecificity of binding to the biologically active isomers of beta-adrenergic agonists. Further evidence derived from the differential potency of binding displacement by the various beta-adrenergic agonists and selective beta 1- and beta 2-adrenergic antagonists indicates that beta-adrenergic receptors of pig cerebral microvessels are mostly of the beta 2-subtype.
TL;DR: The results support the previous conclusion that the pathogenesis of cell damage in hypoglycemia is different from that in hypoxia-ischemia and indicate that other mechanisms than energy failure must contribute to neuronal celldamage in the brain.
Abstract: Previous results have shown that severe, prolonged hypoglycemia leads to neuronal cell damage in, among other structures, the cerebral cortex and the hippocampus but not the cerebellum. In order to study whether or not this sparing of cerebellar cells is due to preservation of cerebellar energy stores, hypoglycemia of sufficient severity to abolish spontaneous EEG activity was induced for 30 and 60 min. At the end of these periods of hypoglycemia, as well as after a 30 min recovery period, cerebellar tissue was sampled for biochemical analyses or for histopathological analyses or for histopathological analyses by means of light and electron microscopy. After 30 min of hypoglycemia. the cerebellar energy state, defined in terms of the phosphocreatine, ATP, ADP, and AMP concentrations, was better preserved than in the cerebral cortex. After 60 min, gross deterioration of cerebellar energy state was observed in the majority of animals, and analyses of carbohydrate metabolites and amino acids demonstrated extensive consumption of endogenous substrates. In spite of this metabolic disturbance, histopathologic alterations were surprisingly discrete. After 30 min, no clear structural changes were observed. After 60 min, only small neurons in the molecular layer (basket cells) were affected, while Purkinje cells and granule cells showed few signs of damage. The results support our previous conclusion that the pathogenesis of cell damage in hypoglycemia is different from that in hypoxia-ischemia and indicate that other mechanisms than energy failure must contribute to neuronal cell damage in the brain.
TL;DR: The findings suggest that rCBF declines during immobilization stress because of cerebrovascular constriction caused by a reduction in Paco2, and that werePaco2 to remain unchanged during immobilized, r CBF would increase by at most 20%.
Abstract: Immobilization stress of conscious, normotensive, freely breathing 10-month-old Wistar-Kyoto rats produced an overall decline in regional cerebral blood flow (rCBF), as measured with [14C]iodoantipyrine, except at the frontal lobe. In 14 brain regions, rCBF fell by an average of 14.3% after 5 min of immobilization and by 11.9% after 15 min. Immobilization stress also stimulated hyperventilation and thereby reduced PaCO2. The slope relating rCBF to PaCO2 averaged 1.5 ml 100 g-1 min-1 mm Hg-1 in 9 significantly affected regions. The findings suggest that rCBF declines during immobilization stress because of cerebrovascular constriction caused by a reduction in PaCO2. Comparison of the average slope with published values in indicates furthermore that were PaCO2 to remain unchanged during immobilization, rCBF would increase by at most 20%.
TL;DR: The data showed that ventilation with 70–80% N2O significantly decreased CBF in several structures (inferior colliculus, superior olive, hippocampus, amygdala, septal nuceli, and hypothalamus), and in some of these, the effects of 70– 80% N 2O and of immobilization were obviously additive.
Abstract: In order to evaluate the effect of 70–80% N2O on local cerebral blood flow (l-CBF) in the rat brain, we developed a procedure for measuring CBF by an autoradiographic [14C]iodoantipyrine technique in awake, minimally restrained animals. Results on l-CBF, as measured in 22 different structures, showed little variability between animals. In the majority of structures analyzed, 70–80% N2O failed to alter l-CBF. These included all cerebral cortical and most subcortical structures. However, nitrous oxide reduced CBF in the the inferior colliculus and the superior olive, in two of the limbic structures analyzed, and in the hypothalamus. In no structure, except the striatum (p < 0.05), was a significant increase in l-CBF obtained in N2O-breathing animals. However, the results suggest that CBF may have been increased in the auditory cortex. Immobilization was found to reduce l-CBF in the cerebellum, inferior colliculus, superior olive, hippocampus, and septal nuclei. The results also suggest that the procedure so...
TL;DR: A theoretical assessment is made of the validity of assumptions underlying the theory for estimating local cerebral blood flow with diffusible tracer in the tissue under normal and ischemic conditions, and it is suggested that contrary to common belief, λ appears to change very little in ischemia if the tissue constituents remain unchanged, whereas m does change with ischemian if the diffusable tracer used is greatly diffusion-limited in the exchange between brain and blood.
Abstract: A theoretical assessment is made of the validity of assumptions underlying the theory for estimating local cerebral blood flow with diffusible tracer in the tissue under normal and ischemic conditions. First, Kety's derivation of equations that have commonly been used for calculating local cerebral blood flow values is examined in order to define the problems and assumptions. Second, the brain:blood partition coefficient of diffusible tracer, λ and the diffusion-limited factor, m, under normal and ischemic conditions are reviewed. An examination of the literature suggested that contrary to common belief, λ appears to change very little in ischemia if the tissue constituents remain unchanged, whereas m does change with ischemia if the diffusible tracer used is greatly diffusion-limited in the exchange between brain and blood. Even when a gas with an m value close to unity is used as the diffusible tracer, the prolonged mean transit time of blood through the ischemic tissue would make it difficult to mainta...
TL;DR: Regional cerebral blood flow was studied in 16 normal adult volunteers during rest and in 10 the study was repeated during skilled hand movements with a fast-rotating, single-photon emission computerized tomograph with four detector heads.
Abstract: Regional cerebral blood flow (CBF) was studied in 16 normal adult volunteers during rest and in 10 the study was repeated during skilled hand movements. A fast-rotating (''dynamic''), single-photon emission computerized tomograph (ECT) with four detector heads was used. Xenon-133 was inhaled over a 1-min period at a concentration of 10 mCi/L. The arrival and washout of the radioisotope was recorded during four 1-min periods. Two slices, 2 cm thick, 7 and 12 cm above the orbitomeatal line were obtained in every study. CBF averaged 60 ml/100 g/min (SD +/- 11) in the lower slice and 51 ml/100 g/min (SD +/- 13) in the upper slice. A symmetric pattern comparing right to left sides was found in both slices. Finger tapping and writing with the right hand increased CBF in specific areas of the upper slice: in the contralateral hand area by 35 +/- 15% (p less than 0.025), and in the supplementary motor area on both sides by 34 +/- 15% (p less than 0.025).
TL;DR: It is concluded that severe hypoglycemia disrupts intracellular pH regulation in the brain and that hypocapnia combined with moderate hypotension leads to an excessive intrACEllular alkalosis of potential importance for the development of cell damage.
Abstract: Severe hypoglycemia is associated with a marked curtailment of cerebral glucose supply and with consumption of endogenous carbohydrate metabolites and amino acids, many of which exist as anions of acids. Since metabolic control of intracellular pH in acute hypo- and hypercapnia seems to be dependent on the production and consumption of metabolic acids, it must be suspected that intracellular pH in the brain is poorly regulated in hypoglycemic animals. We induced hypocapnia (Paco2 about 15 mm Hg) and hypercapnia (Paco2 about 90 mm Hg) in insulin-injected animals in “precoma” (EEG pattern of slow waves, polyspikes) and “coma” (cessation of EEG activity) and measured CSF and intracellular acid-base changes using the CO2 method.The induced hypoglycemia did not measurably alter CSF acid-base changes from the normal during hypercapnia, but it did impair CSF pH regulation in hypocapnia. Animals in precoma showed an unchanged cerebral energy state during both hypo- and hypercapnia. Regulation of intracellular pH ...
TL;DR: It is suggested that increases in cerebral blood flow produced by histamine are the result of stimulation of vascular H1- and H2-receptors, rather than a secondary response to metabolic activation.
Abstract: Summary: We examined the cerebral circulatory effects of intra-carotid infusion of histamine or its receptor agonists in anesthetized rats. Cerebral blood flow was measured by two methods: an intracarotid 133Xe clearance technique and tissue sampling after systemic administration of the diffusible tracer, [14C]iodoantipyrine. Brain metabolic responses were estimated by the 2-deoxyglucose method and tissue sampling. Intracarotid infusion of histamine when the blood-brain barrier was intact did not increase cerebral blood flow. Following disruption of the blood-brain barrier by carotid injection of hypertonic urea, histamine evoked dose-dependent increases (133Xe clearance method) in cerebral blood flow to a maximum of 50% (20 /ug min-1 kg-1); histamine produced increases in blood flow to areas supplied by the internal carotid artery, e.g., thalamus and parietal cortex ([14C]iodoantipyrine method). Both classes of histamine receptors (H! and H2) participated in mediating increases in cerebral blood flow after blood-brain barrier opening. Mepyramine (Hrantagonist) and metiamide (H2-antagonist) attenuated blood flow responses to histamine infusion (133Xe clearance method); metiamide was the more effective blocking agent. Pyridylethylamine (Hragonist) and dimaprit (H2-agonist) both caused increases in regional cerebral blood flow ([14C]iodoantipyrine method). Histamine infusion after blood-brain barrier opening did not increase cerebral glucose consumption. We suggest that increases in cerebral blood flow produced by histamine are the result of stimulation of vascular Hr and H2-receptors, rather than a secondary response to metabolic activation.
TL;DR: The need for a high quality journal specializing in brain circulation and metabolism was discussed, and it was agreed that a new journal should be started, entitled Journal of Cerebral Blood Flow and Metabolism, and that Murray Harper be asked to take the position of Chief Editor.
Abstract: Those of us who have attended or closely watched the series of international meetings on cerebral circulation and metabolism initiated by David Ingvar and Niels Lassen in 1965 have seen the growth and maturation of a new field which has become increasingly interdisciplinary. Initially these meetings placed a clear emphasis on cerebral circulation, undoubtedly due to the fact that a new technology had become available for measurements of regional cerebral blood flow in man and experimental animals. As time went by, an increasing number of communications on cerebral metabolism were presented at these meetings. Furthermore, during recent years many contributions have concerned, wholly or in part, topics that by conventional standards belong to the fields of neurohistology and neuropharmacology. Many of those who work within this multidisciplinary and rapidly growing field must be distressed by the difficulty that exists in following the relevant literature. Important articles are found scattered throughout journals of brain sciences, circulatory and general physiology, neurochemistry, and neuropharmacology, a significant fraction also appearing in clinical journals of anesthesiology, neurology, and neurosurgery. About three years ago Lou Sokoloff and I started discussing the need for a high quality journal specializing in brain circulation and metabolism. Our attitude at the beginning was somewhat ambivalent since we realized that a new journal, unless highly successful, might aggravate rather than improve the existing communication problem. Two things made us proceed with the initial rather vague plans. First, informal discussions with a number of senior research workers within the field disclosed an unexpectedly positive reaction. Second, it turned out that we could persuade just the right person to take on the crucial position as Chief Editor. In March 1980, on the occasion of a scientific meeting in Paris, the plans for a new journal were discussed by a group often people (Fieschi, Hossmann, Ingvar, Klatzo, Lassen, MacKenzie, Raichle, Reivich, Siesjo, and Sokoloff). It was agreed that a new journal should be started, entitled Journal of Cerebral Blood Flow and Metabolism, and that Murray Harper be asked to take the position of Chief Editor. Two members of the group were asked to approach one publisher each, exploring their interest in issuing the journal. The important (and delicate) matter of collecting an editorial board was discussed. The problem was approached the following way. At the Paris meeting, and in subsequent correspondence, a tentative list of more than 50 names was drawn up. This list was then circulated to members of the ad hoc committee, each one being asked to tick off those 25 individuals they considered should constitute the initial editorial board. This ballot, and consultations with some others, resulted in the board which now exists. It should be emphasized that the Chief Editor particularly asked not to be involved in choosing the board members. Needless to say, the composition of the board represents a compromise between many requirements (adequate coverage of the field, geographical balance and, last but not least, willingness to serve actively on the board). INTRODUCTION In the discussions about the journal, many emphasized that it would be desirable to form an International Society of Cerebral Circulation and Metabolism, and that the proposed journal should be the official organ of that society. It was suggested that a nucleus of a small group of people be constituted who could serve on a provisional council until the next meeting in St. Louis. Discussions led to the proposal that a Steering Committee be set up, consisting of four members of the original International Advisory Board (Lassen, Ingvar, Plum, and Fieschi) plus another six names (Harper, Hossmann, Raichle, Reivich, Siesjo, and Sokoloff). This Steering Committee took the responsibility for formally concluding the successful negotiations with Raven Press. The Committee (with Murray Harper excluded) also authorized the nomination of the Chief and Assistant Editors, the Deputy Chief Editors, and the members of the Editorial Board. There was a unanimous vote that Seymour Kety should be invited to be Honorary Editor. Finally, the members of the committee reached an agreement about the policy of the journal, and decided that membership in the Society should include a personal subscription to the journal. Those of us who have been engaged in initiating the journal have done so because we feel it will serve a useful purpose in bringing together the most important articles within our fields of interest. The foundation of the new Society is inspired by the same philosophy, i.e., by the belief that research progress in these fields will be furthered by improved means of communication between scientists who differ in their methodological approach but unite in their efforts to unravel the secrets of cerebral circulation and metabolism in health and disease. The start has been made and the founders have to take the responsibility for the initial momentum. However, the success of the journal and the Society depends heavily on those who are willing to go through the effort of submitting their work to a journal which strives for quality in scientific standards.
TL;DR: The effects of pentobarbital on the contractile responses of isolated feline middle cerebral arteries have been examined and the results caution against the use of pentbarbital as an anaesthetic agent in investigations of cerebrovascular reactivity.
Abstract: The effects of pentobarbital on the contractile responses of isolated feline middle cerebral arteries have been examined. In the presence of pentobarbital (3 x 10(-4)M), the maximum contractions effected by potassium, noradrenaline, and prostaglandin F2 alpha were reduced by 37 +/- 3, 69 +/- 3, and 10 +/- 6%, respectively. The results caution against the use of pentobarbital as an anaesthetic agent in investigations of cerebrovascular reactivity.
TL;DR: The results demonstrate that HV-LV shifts, whether spontaneous or stimulation-induced, are associated with significant increases in both cerebral blood flow and cerebral oxygen uptake, and suggest that the cerebral vasodilatation that occurs during the early phase of HV -LV shifts involves cholinergic mechanisms.
Abstract: In the present study, the relationships among electroencephalographic (EEG) amplitude shifts, cerebral blood flow (CBF), and cerebral oxygen uptake (CMRO2) have been characterized in halothane-anes...
TL;DR: The results hint that part of the resistance of the cerebellum to the hypoglycemic insult may be due to a better preserved Ca2+ homeostasis and/or a less pronounced activation of phospholipase A2.
Abstract: Previous results from this laboratory have shown that although prolonged severe hypoglycemia (30 or 60 min with cessation of electroencephalographic activity) leads to relatively extensive energy f...
TL;DR: Indomethacin induced a highly significant decrease in CBF during hypercapnia, demonstrating that the barbiturate does not eliminate the effect of indomethACin on CO2 responsiveness and suggesting that a reduction of this magnitude will escape detection with some CBF techniques in current use.
Abstract: Summary: Although results obtained in baboons and rats have demonstrated that the fatty acid cyclo-oxygenase inhibitor indomethacin reduces cerebral blood flow (CBF) under control conditions and markedly attenuates the CBF response to hypercapnia, nonconfirmatory results have been obtained in rab bits and cats. Since these latter studies were carried out under barbiturate anesthesia, we tested the effect of indomethacin (10 mg kg-I) on CBF and cerebral oxygen consumption in rats anesthetized with 150 mg kg-1 of phenobarbital. At normocapnia the barbiturate reduced CBF, measured with a 133Xe modification of the Kety-Schmidt technique, to about 50% of nitrous oxide control values as previously determined with a similar technique. At this CBF level, indomethacin induced a small, albeit highly significant decrease in CBF, We suggest that a reduction of this magnitude will escape detection with some CBF techniques in current use. Indomethacin induced a highly significant decrease in CBF during hypercapnia, demonstrating that the barbiturate does not eliminate the effect of indomethacin on CO2 responsiveness. The magnitude of the reduction in CO2 response was so large that it should be detected with most methods for measuring CBF. A comparison with previous data on animals under 70% N20 demonstrated that phenobarbital reduced the CO2 respon siveness, defined as the ratio llCBFI llPC02, to 39% of that observed under nitrous oxide analgesia. With both types of anesthesia, indomethacin curtailed the CO2 responsiveness 4-to 5-fold. Key Words: Cerebral blood flow Cerebral metabolic rate-Normocapnia -Hypercapnia-Ind omethacin. In spite of the fact that the problem has been studied over many decades, the factors that adjust the cerebral blood flow (CBF) to functional and metabolic demands have not yet been defined. Re cent results indicate that some of these missing coupling factors may be provided by products of the fatty acid cyclo-oxygenase, i. e., by prostaglandins and related substances. The evidence comes from Address correspondence and reprint requests to Dr. Dahlgren at Research Department 4, E-Blocket, University Hospital, S-221 85 Lund, Sweden. Abbreviations used: Cao2, oxygen content; A VD02, ar teriovenous oxygen difference.