The effect of hypovolemic hypotension on extra- and intracellular acid-base parameters and energy metabolites in the rat brain.
TL;DR: The results strongly speak against the possibility that the decrease in cerebrovascular resistance, which occurs during autoregulation of flow in hypovolemic hypotension, is related to extracellular pH changes.
Abstract: Siesjo, B. K. and N. N. Zwetnow. The effect of hypovolemic hypotension on extra-and intracellular acid-base parameters and energy metabolites in the rat brain. Acta physiol. scand. 1970. 79. 114–124.
The influence of hypovolemic decreases in the mean arterial pressure upon intra- and extracellular acid-base parameters in the brain, and upon tissue concentrations of ATP, ADP, AMP and phosphocreatine, was studied in immobilized and artificially ventilated rats. Hypotensive periods of 20 or 60 min duration did not lead to any significant changes in ATP, ADP, AMP or phosphocreatine concentrations until the mean arterial pressure was below 40 mm Hg, but there was a small gradual increase in tissue lactate concentration, and in the lactate/pyruvate ratio, even at a moderate decrease in blood pressure. The lactate and pyruvate changes were significant even after corrections for blood and CSF lactate and pyruvate contents, and similar changes were seen in the CSF. The moderate changes in extra- and intracellular lactate concentrations did not lead to any noticeable decreases in calculated extra- and intracellular pH values since even moderate reductions in blood pressure usually led to small concomitant falls in the tissue CO2 tension. Thus, if it can be assumed that the cerebral blood flow was upheld at the moderately reduced perfusion pressures, the results strongly speak against the possibility that the decrease in cerebrovascular resistance, which occurs during autoregulation of flow in hypovolemic hypotension, is related to extracellular pH changes.
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TL;DR: Differences in the pump/leak relationship for calcium explain why calcium and glutamate antagonists may lack effect on the cardiac arrest type of ischemia, while decreasing infarct size in focal ischemIA.
Abstract: ✓ The mechanisms that give rise to ischemic brain damage have not been definitively determined, but considerable evidence exists that three major factors are involved: increases in the intercellular cytosolic calcium concentration (Ca++i), acidosis, and production of free radicals. A nonphysiological rise in Ca++i due to a disturbed pump/leak relationship for calcium is believed to cause cell damage by overactivation of lipases and proteases and possibly also of endonucleases, and by alterations of protein phosphorylation, which secondarily affects protein synthesis and genome expression. The severity of this disturbance depends on the density of ischemia. In complete or near-complete ischemia of the cardiac arrest type, pump activity has ceased and the calcium leak is enhanced by the massive release of excitatory amino acids. As a result, multiple calcium channels are opened. This is probably the scenario in the focus of an ischemic lesion due to middle cerebral artery occlusion. Such ischemic tissues ca...
1,136 citations
TL;DR: The pathophysiology of lesions caused by focal cerebral ischemia, a complex interplay between loss of cellular calcium homeostasis and acidosis, plays an important role in the pathogenesis of ischemic cell damage.
Abstract: This article examines the pathophysiology of lesions caused by focal cerebral ischemia. Ischemia due to middle cerebral artery occlusion encompasses a densely ischemic focus and a less densely ischemic penumbral zone. Cells in the focus are usually doomed unless reperfusion is quickly instituted. In contrast, although the penumbra contains cells "at risk," these may remain viable for at least 4 to 8 hours. Cells in the penumbra may be salvaged by reperfusion or by drugs that prevent an extension of the infarction into the penumbral zone. Factors responsible for such an extension probably include acidosis, edema, K+/Ca++ transients, and inhibition of protein synthesis. Central to any discussion of the pathophysiology of ischemic lesions is energy depletion. This is because failure to maintain cellular adenosine triphosphate (ATP) levels leads to degradation of macromolecules of key importance to membrane and cytoskeletal integrity, to loss of ion homeostasis, involving cellular accumulation of Ca++, Na+, and Cl-, with osmotically obligated water, and to production of metabolic acids with a resulting decrease in intra- and extracellular pH. In all probability, loss of cellular calcium homeostasis plays an important role in the pathogenesis of ischemic cell damage. The resulting rise in the free cytosolic intracellular calcium concentration (Ca++) depends on both the loss of calcium pump function (due to ATP depletion), and the rise in membrane permeability to calcium. In ischemia, calcium influx occurs via multiple pathways. Some of the most important routes depend on activation of receptors by glutamate and associated excitatory amino acids released from depolarized presynaptic endings. However, ischemia also interfers with the intracellular sequestration and binding of calcium, thereby contributing to the rise in intracellular Ca++. A second key event in the ischemic tissue is activation of anaerobic glucolysis. The main reason for this activation is inhibition of mitochondrial metabolism by lack of oxygen; however, other factors probably contribute. For example, there is a complex interplay between loss of cellular calcium homeostasis and acidosis. On the one hand, a rise in intracellular Ca++ is apt to cause mitochondrial accumulation of calcium. This must interfere with ATP production and enhance anaerobic glucolysis. On the other hand, acidosis must interfere with calcium binding, thereby contributing to the rise in intracellular Ca++.
790 citations
TL;DR: It is emphasized that gross brain damage, involving edema formation and infarction, is enhanced by tissue acidosis, and that neuronal damage appears related to a disturbed Ca2+ homeostasis, and to Ca2-triggered events such as lipolysis and proteolysis.
Abstract: Recent developments in the field of cerebral circulation and metabolism are reviewed, with emphasis on circulatory and metabolic events that have a bearing on brain damage incurred in ischemia. The first part of the treatise reviews aspects of cerebral metabolism that provide a link to the coupling of metabolism and blood flow, notably those that lead to a perturbation of cellular energy state, ionic homeostasis, and phospholipid metabolism. In the second part, attention is focused on the derangement of energy metabolism and its effects on ion fluxes, acid-base homeostasis, and lipid metabolism. It is emphasized that gross brain damage, involving edema formation and infarction, is enhanced by tissue acidosis, and that neuronal damage, often showing a pronounced selectivity in localization, appears related to a disturbed Ca2+ homeostasis, and to Ca2+-triggered events such as lipolysis and proteolysis.
547 citations
TL;DR: Lowering the concentration of oxygen or of glucose to which mouse and rat brains were exposed impaired the synthesis of acetylcholine from labelled precursors in vivo.
Abstract: — Lowering the concentration of oxygen or of glucose to which mouse and rat brains were exposed impaired the synthesis of acetylcholine from labelled precursors in vivo.
Histotoxic hypoxia induced with KCN or anemic hypoxia induced with NaNO2 (to oxidize hemoglobin to methemoglobin) reduced incorporation of [2H4]choline into acetylcholine. This change in acetylcholine metabolism occurred with doses of KCN or NaNO2 which did not alter the concentrations of ATP or ADP or the adenylate energy charge. Hypoglycemia induced by large doses of insulin also reduced the incorporation of [2H4]choline into acetylcholine. Both hypoxia and hypoglycemia increased the concentration of choline in the brain. The specific activity of choline did not decrease in hypoxia; it did not decrease enough in hypoglycemia to explain the reduced incorporation of [2H4]choline into acetylcholine.
Pretreatment with the cholinesterase inhibitor physostigmine delayed the onset of both seizures and death in mice after induction of hypoxia by large doses of NaNO2. Pretreatment with physostigmine also decreased the number of mice dying within 3 h after the induction of hypoglycemia with large doses of insulin. These observations suggest that the effects of hypoxia and hypoglycemia interfere with the synthesis of a critical pool of acetylcholine.
The incorporation of labelled precursors into acetylcholine related linearly to both the cytoplasmic redox state (NAD/NADH ratio) and to the NAD/NADH potential across the mitochondrial membrane. The redox potential of NAD/NADH in the cytoplasm was calculated from the [pyruvate]/[lactate] equilibrium and the redox potential of NAD/NADH in the mitochondria from the [NH4][2-oxoglutar-ate]/[glutamate] equilibrium. The potential across the mitochondrial membrane was calculated from the difference.
These observations indicate that carbohydrate oxidation is one of the factors on which the synthesis of the neurotransmitter acetylcholine depends closely in mouse and rat brain.
303 citations
TL;DR: Carohydrate substrates, organic phosphates, amino acids and ammonia were studied in the rat brain during complete ischemia of 1–15 min duration utilising an ischemic model with increase of the intracranial CSF pressure to suggest citric acid cycle intermediates in general were diverted towards amino acid formation.
289 citations
References
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TL;DR: This is a record of the concentrations of the nonenzyme components of the Embden-Meyerhof system in mouse brain measured at brief intervals after the production of complete ischemia by decapitation, which resulted in increases in glycolytic rates of at least 4to 7-fold in different experimental groups of mice.
2,179 citations
TL;DR: In the present study great emphasis will be put on information regarding cerebral oxygen consumption in man, whereas only scant attention will be paid to the intermediary metabolism of the brain.
Abstract: HE BLOOD FLOW AND OXYGEN METABOLISM of the human brain has been studied intensively since Kety developed the inert gas method in 1945. More than 200 clinical studies employing this method have been published so far, and now the former terra incognita is well mapped out. The information gained from all these studies will form the subject of the present review. It will also include, however, the results obtained by an indicator injection technique which has been applied to the measurement of cerebral blood flow in man to a much more limited extent. The early results obtained in this particular field have been reviewed by Schmidt (292) and Kety (156-163) and by other authors (38, 61, 76, 2 I 6, 281, 307). The aim of the present review is to offer an up to date presentation of the subject, and, in particular, to discuss certain aspects in greater detail. The general field of cerebral circulation was reviewed by Wolff in 1936 (348), by many authors in a comprehensive study in 1938 (41), and extensive bibliographic compilations of original contributions from 1938 to 1952 have also been published (255, 256). The pharmacology of the cerebral circulation alone, which has recently been reviewed by Sokoloff (318), forms an overwhelming body of knowledge. In the present study great emphasis will be put on information regarding cerebral oxygen consumption in man, whereas only scant attention will be paid to the intermediary metabolism of the brain. Himwich in I 951 published an excellent review (142) of much of the pertinent literature in this rapidly expanding field. Reference is also made to the recent study by Sokoloff (3 I 9). The first attempt to measure the cerebral blood flow in man was made in 1941 by observing the displacement of spinal fluid caused by compression of the
1,852 citations
TL;DR: The bearing of these findings on various problems, including the number of NAD(+)-NADH pools in liver cells; the applicability of the method to tissues other than liver; the transhydrogenase activity of glutamate dehydrogenase; the physiological significance of the difference of the redox states of mitochondria and cytoplasm; aspects of the regulation of theredox state of cell compartments; the steady-state concentration of mitochondrial oxaloacetate.
Abstract: 1. The concentrations of the oxidized and reduced substrates of the lactate-, β-hydroxybutyrate- and glutamate-dehydrogenase systems were measured in rat livers freeze-clamped as soon as possible after death. The substrates of these dehydrogenases are likely to be in equilibrium with free NAD+ and NADH, and the ratio of the free dinucleotides can be calculated from the measured concentrations of the substrates and the equilibrium constants (Holzer, Schultz & Lynen, 1956; Bucher & Klingenberg, 1958). The lactate-dehydrogenase system reflects the [NAD+]/[NADH] ratio in the cytoplasm, the β-hydroxybutyrate dehydrogenase that in the mitochondrial cristae and the glutamate dehydrogenase that in the mitochondrial matrix. 2. The equilibrium constants of lactate dehydrogenase (EC 1.1.1.27), β-hydroxybutyrate dehydrogenase (EC 1.1.1.30) and malate dehydrogenase (EC 1.1.1.37) were redetermined for near-physiological conditions (38°; I0·25). 3. The mean [NAD+]/[NADH] ratio of rat-liver cytoplasm was calculated as 725 (pH7·0) in well-fed rats, 528 in starved rats and 208 in alloxan-diabetic rats. 4. The [NAD+]/[NADH] ratio for the mitochondrial matrix and cristae gave virtually identical values in the same metabolic state. This indicates that β-hydroxybutyrate dehydrogenase and glutamate dehydrogenase share a common pool of dinucleotide. 5. The mean [NAD+]/[NADH] ratio within the liver mitochondria of well-fed rats was about 8. It fell to about 5 in starvation and rose to about 10 in alloxan-diabetes. 6. The [NAD+]/[NADH] ratios of cytoplasm and mitochondria are thus greatly different and do not necessarily move in parallel when the metabolic state of the liver changes. 7. The ratios found for the free dinucleotides differ greatly from those recorded for the total dinucleotides because much more NADH than NAD+ is protein-bound. 8. The bearing of these findings on various problems, including the following, is discussed: the number of NAD+–NADH pools in liver cells; the applicability of the method to tissues other than liver; the transhydrogenase activity of glutamate dehydrogenase; the physiological significance of the difference of the redox states of mitochondria and cytoplasm; aspects of the regulation of the redox state of cell compartments; the steady-state concentration of mitochondrial oxaloacetate; the relations between the redox state of cell compartments and ketosis.
1,671 citations
TL;DR: The results from previous studies concerning the principal effects of arterial carbon dioxide tension and oxygen saturation on cerebral blood flow were confirmed and it was demonstrated that autoregulation of flow occurred within wide pressure limits under normo- and hypocapnia.
Abstract: Effects of arterial carbon dioxide tension and oxygen saturation on cerebral blood flow autoregulation in dogs. Acta physiol. scand. 1965. 66. Suppl. 258. 27–53. - Pressure-flow relation- ships of the cerebral circulation under influence of variations in arterial carbon dioxide tension and oxygen saturation were studied in pentobarbital anaesthetized dogs. Cerebral blood flow was measured by recording of the γ- emission of radioactive krypton (Kr85), which was injected into the vertebral artery. The recorded desaturation curve was resolved into two exponential phases and the fast phase was considered as representative of blood flow in the grey matter of the brain. It was demonstrated that autoregulation of flow occurred within wide pressure limits under normo- and hypocapnia. Auto-regulation was less pronounced under hypercapnia and was abolished at low arterial oxygen saturation. Possible mechanisms of autoregulation of cerebral blood flow are discussed. Evidences are presented which speak against the theory that changes in the carbon dioxide tension are the main cause of this autoregulation. The results from previous studies concerning the principal effects of arterial carbon dioxide tension and oxygen saturation on cerebral blood flow were confirmed.
270 citations
TL;DR: In cat experiments measurements were made of the CO2 tensions in arterial and cerebral venous blood, in cisternal cerebrospinal fluid (CSF), and on the surface of the cerebral cortex, it was found that both the CSF CO2 tension and theCO2 tension measured on thesurface of the brain exceeded the arithmetic mean.
Abstract: In cat experiments measurements were made of the CO2 tensions in arterial and cerebral venous blood, in cisternal cerebrospinal fluid (CSF), and on the surface of the cerebral cortex. It was found that both the CSF CO2 tension and the CO2 tension measured on the surface of the brain exceeded the arithmetic mean of the arterial and the venous CO2 tensions by 0.5–1 mm Hg. This means that the CSF and the cortical surface CO2 tensions coincided with the mean tissue CO2 tension, which can be calculated from the diffusion equations, and they were distinctly different from the cerebral venous CO2 tension.
The arterio-venous PCO2 difference was found to change linearly from 12 to 4 mm Hg when the arterial CO2 tension increased from 30 to 90 mm Hg. The arterio-venous difference was found to be very sensitive to the experimental conditions. Thus, it was influenced by the craniotomy and the other procedures connected with the tissue measurements, and also by the sampling of CSF.
It is recommended that mean tissue CO2 tensions in the brain are obtained by means of direct measurements on cisternal CSF, or by means of calculation from the arterial and the cerebral venous CO2 tensions. In the latter case, a fairly exact value is obtained by adding 1 mm Hg to the arithmetic mean of the blood tensions. Tissue measurements are recommended for studies of CO2 transients, or for conditions with a disturbed local circulation. If none of these measurements are feasible, the tissue CO2 tension can be approximately calculated from the arterial CO2 tension, as described in the text.
156 citations