Kinetic Analysis of the Human Blood-Brain Barrier Transport of Lactate and its Influence by Hypercapnia

Knudsen, Gitte M.; Paulson, Olaf B.; Hertz, Marianne M.

doi:10.1038/jcbfm.1991.107

Cited by 69 publications

(45 citation statements)

References 14 publications

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“…Early work in anesthetized animals showed that lactate crosses the bloodbrain barrier by facilitated diffusion in a stereospecific and saturable manner, and the rate of lactate uptake is much lower than that of glucose (28). However, more recent studies in awake animals and humans demonstrated that the average brain uptake of lactate in resting brain is approximately seven times higher than previously calculated (28), reaching Ϸ50% of that of glucose (29,30). Although entry of lactate from plasma into resting brain is more rapid than previously thought (31), Lear and Kasliwal (32) have shown that the local transport of lactate is further increased during brain activation, which could lead to an increased effect of the injected lactate.…”

Section: Discussionmentioning

confidence: 92%

Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain

Mintun

Vlassenko

Rundle

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

132

104

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The factors regulating cerebral blood flow (CBF) changes in physiological activation remain the subject of great interest and debate. Recent experimental studies suggest that an increase in cytosolic NADH mediates increased blood flow in the working brain. Lactate injection should elevate NADH levels by increasing the lactate͞ pyruvate ratio, which is in near equilibrium with the NADH͞NAD ؉ ratio. We studied CBF responses to bolus lactate injection at rest and in visual stimulation by using positron-emission tomography in seven healthy volunteers. Bolus lactate injection augmented the CBF response to visual stimulation by 38 -53% in regions of the visual cortex but had no effect on the resting CBF or the wholebrain CBF. These lactate-induced CBF increases correlated with elevations in plasma lactate͞pyruvate ratios and in plasma lactate levels but not with plasma pyruvate levels. Our observations support the hypothesis that an increase in the NADH͞NAD ؉ ratio activates signaling pathways to selectively increase CBF in the physiologically stimulated brain regions.T he nature of the link between cerebral blood flow (CBF) and energy metabolism is of great interest and importance but remains controversial despite decades of research and debate. Although CBF augmentation is still considered to be a hallmark of intensified neural activity, previous assumptions that behaviorally induced increases in local blood flow reflect similar local increases in oxidative metabolism (1) have been contradicted by brain imaging studies with positron-emission tomography (PET) (2, 3) and functional MRI (4). Fox and his colleagues (2, 3) demonstrated that in normal, awake adult humans, stimulation of the visual or somatosensory cortex results in dramatic increases in CBF but minimal increases in oxygen consumption. Increases in glucose utilization are similar to changes in CBF (3, 5). Although it is often assumed that the increase in CBF in neural activation is driven by a need for increased delivery of oxygen or glucose, it has been demonstrated in human subjects that the CBF response to physiological activation is not altered by either stepped hypoglycemia (6) or hypoxia (7). These results suggest that increased CBF during physiological brain activation does not occur to prevent a shortage of these metabolic substrates. Ido et al. (8) recently reported that CBF in activated rat brain is modified by changes in the plasma lactate͞pyruvate ratio: CBF was augmented when lactate͞pyruvate ratios were raised and attenuated when the ratios were lowered. Specifically, immediately after lactate bolus injection, the magnitude of the CBF increase associated with sensory stimulation approximately doubled. Based on the near equilibrium between the ratios of lactate͞pyruvate and cytosolic free NADH͞NAD ϩ (which reflects the local environment redox state) (9), they suggested that cytosolic free NADH is an important trigger or sensor of blood flow. The reoxidation of NADH to NAD ϩ is a step of vital importance for brain cells, especially in the acti...

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Section: Discussionmentioning

confidence: 92%

Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain

Mintun

Vlassenko

Rundle

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

132

104

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“…Assuming a brain Lac concentration of 1 mmol/g, a pseudo first-order rate constant k Lac = 0.09 min À1 can be estimated from the reported exchange rate of 0.09 mmol/g/min (Knudsen et al, 1991). The maximal Lac efflux is thus k Lac * D[Lac] = 0.018 mmol/g/min, which corresponds to 8% of the increased Pyr derived from Glc.…”

Section: Discussionmentioning

confidence: 99%

Sustained Neuronal Activation Raises Oxidative Metabolism to a New Steady-State Level: Evidence from ¹H NMR Spectroscopy in the Human Visual Cortex

Mangia

Tkáč

Gruetter

et al. 2007

J Cereb Blood Flow Metab

263

394

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To date, functional 1 H NMR spectroscopy has been utilized to report the time courses of few metabolites, primarily lactate. Benefiting from the sensitivity offered by ultra-high magnetic field (7 T), the concentrations of 17 metabolites were measured in the human visual cortex during two paradigms of visual stimulation lasting 5.3 and 10.6 mins. Significant concentration changes of approximately 0.2 lmol/g were observed for several metabolites: lactate increased by 23%65% (P < 0.0005), glutamate increased by 3%61% (P < 0.01), whereas aspartate decreased by 15%66% (P < 0.05). Glucose concentration also manifested a tendency to decrease during activation periods. The lactate concentration reached the new steady-state level within the first minute of activation and came back to baseline only after the stimulus ended. The changes of the concentration of metabolites implied a rise in oxidative metabolism to a new steady-state level during activation and indicated that amino-acid homeostasis is affected by physiological stimulation, likely because of an increased flux through the malate-aspartate shuttle.

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“…This could be caused by inhibition of cerebral lactate uptake mediated by the increase in pH during hyperventilation. 33 However, increased outward flux compared with inward flux of lactate at the monocarboxylate carrier transport system cannot be excluded. In the present study, LOI decreased, but remained positive, indicating aerobic cerebral metabolism during short-term hyperventilation.…”

Section: Discussionmentioning

confidence: 99%

Cerebral glucose and oxygen metabolism in patients with fulminant hepatic failure

Strauss¹,

Møller²,

Larsen³

et al. 2003

Liver Transplantation

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Hyperammonemia and hyperventilation are consistent findings in patients with fulminant hepatic failure (FHF), which may interfere with cerebral glucose and oxygen metabolism. The aim of the present study is to evaluate whether cerebral oxidative metabolism is preserved early in the course of FHF and whether hyperventilation has an influence on this. We included 16 patients with FHF, 5 patients with cirrhosis of the liver, and 8 healthy subjects. Concomitant blood sampling from an arterial catheter and a catheter in the jugular bulb and measurement of cerebral blood flow by the xenon 133 wash-out technique allowed calculation of cerebral uptake of glucose (CMR gluc ) and oxygen (CMRO 2 ). Both CMR gluc and CMRO 2 were reduced in patients with FHF compared with those with cirrhosis and healthy subjects, i.e., 11.8 ؎ 2.7 v 18.3 ؎ 5.5 and 28.5 ؎ 6.6 mol/100 g/min (P < .05) and 86 ؎ 18 v 164 ؎ 42 and 174 ؎ 27 mol/100 g/min (P < .05). Arteriovenous difference in oxygen and oxygen-glucose index were normal in patients with FHF. Institution of mechanical hyperventilation did not affect glucose and oxygen uptake and hyperventilation did not affect lactatepyruvate ratio or lactate-oxygen index. In conclusion, we found that cerebral glucose and oxygen consumption are proportionally decreased in patients with FHF investigated before clinical signs of cerebral edema. Our data suggest that cerebral oxidative metabolism is retained at this stage of the disease without being compromised by hyperventilation. (Liver Transpl 2003;9:1244-1252.) F ulminant hepatic failure (FHF) is a critical illness with multiorgan failure and hepatic encephalopathy (HE). Cerebral edema and intracranial hypertension are feared and often fatal complications. The pathophysiological background for these complications is not fully understood, but alterations in cerebral metabolism and cerebral blood flow (CBF) seem to be of importance. 1 Metabolism of the brain is different from most other tissues in several aspects. It uses glucose only as an energy source under normal physiological conditions, and in contrast to most other organs, brain cells are permeable to glucose and can use glucose without the intermediation of insulin. 2 However, when necessary, the brain can use other substrates as energy sources, such as ␤-hydroxybutyrate (␤-OHB) and acetoacetate. 3 Hyperammonemia is a consistent finding in FHF, and arterial ammonia concentration seems to correlate with the development of cerebral edema and intracranial hypertension in patients with FHF. 4 The exact biochemical mechanisms involved in cerebral ammonia toxicity are not fully established, but ammonia-induced alterations in cerebral glucose metabolism may be of importance. 5 In experimental studies of hyperammonemia, both reduced 6,7 and increased 8 cerebral glucose metabolism have been reported. Also, studies of patients with FHF reported both reduced, 9,10 normal, 10 and increased 11 cerebral glucose metabolism, whereas cerebral oxygen metabolism was reduced in all studies. [9][10][11][12] The a...

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Kinetic Analysis of the Human Blood-Brain Barrier Transport of Lactate and its Influence by Hypercapnia

Cited by 69 publications

References 14 publications

Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain

Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain

Sustained Neuronal Activation Raises Oxidative Metabolism to a New Steady-State Level: Evidence from ¹H NMR Spectroscopy in the Human Visual Cortex

Cerebral glucose and oxygen metabolism in patients with fulminant hepatic failure

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Kinetic Analysis of the Human Blood-Brain Barrier Transport of Lactate and its Influence by Hypercapnia

Cited by 69 publications

References 14 publications

Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain

Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain

Sustained Neuronal Activation Raises Oxidative Metabolism to a New Steady-State Level: Evidence from 1H NMR Spectroscopy in the Human Visual Cortex

Cerebral glucose and oxygen metabolism in patients with fulminant hepatic failure

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Sustained Neuronal Activation Raises Oxidative Metabolism to a New Steady-State Level: Evidence from ¹H NMR Spectroscopy in the Human Visual Cortex