Autoradiographic Measurement of Cerebral Lactate Transport Rate Constants in Normal and Activated Conditions

Lear, James L.; Kasliwal, Ravindra

doi:10.1038/jcbfm.1991.106

Cited by 39 publications

(35 citation statements)

References 32 publications

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“…[The minimal impact of pyruvate and lactate injection on flows in unstimulated vs. stimulated retina and visual cortex may be explained by increased transport rate constants for cerebral lactate efflux and influx evoked by neural activity (25).] In contrast to the strong correlation between blood flow and L͞P ratios in stimulated retina, L͞P ratios in stimulated muscle did not correlate with flow.…”

Section: Discussionmentioning

confidence: 45%

NADH augments blood flow in physiologically activated retina and visual cortex

Ido

Chang

Williamson

2004

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

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The mechanism(s) that increase retinal and visual cortex blood flows in response to visual stimulation are poorly understood. We tested the hypothesis that increased transfer of electrons and protons from glucose to cytosolic free NAD ؉ , reducing it to NADH, evoked by increased energy metabolism, fuels redox-signaling pathways that augment flow. The near-equilibrium between free cytosolic NADH͞NAD ؉ and lactate͞pyruvate ratios established by lactate dehydrogenase predicts that transfer of additional electrons and protons from injected lactate to NAD ؉ will augment the elevated blood flows in stimulated retina and cortex, whereas transfer of electrons and protons from NADH to injected pyruvate will attenuate the elevated flows. These predictions were tested and confirmed in rats. Increased flows evoked by stimulation also were prevented by inhibition of nitric oxide synthase. These findings support an important role for cytosolic free NADH in fueling a signaling cascade that increases • NO production, which augments blood flow in photostimulated retina and visual cortex. P hysiological work, ranging from muscle contraction to neural activity in the brain and phototransduction in the retina, increases energy metabolism and blood flow (1-5). The increase in energy metabolism is explained by increased synthesis of ATP to fuel the work performed. However, the metabolic basis for the increase in blood flow remains enigmatic. Until recently it was widely believed that the increased flow was needed to provide more oxygen and glucose to support increased energy metabolism and to remove the products of energy metabolism that inhibit ATP synthesis. However, increased brain blood flow and glucose utilization evoked by neural activity exceed increased oxygen consumption by as much as 10-fold despite normal or elevated oxygen levels (2, 3). And, enhanced flow is not needed to augment glucose uptake for brief periods of neural activity (6-8).Observations in rats support the hypothesis that electrons and protons (E&P) carried by free cytosolic NAD (NAD c ) mediate increased blood flows in contracting skeletal muscle and in stimulated whisker barrel cerebral cortex (1); varying the rates of transfer of E&P to and from free NAD c evokes corresponding changes in flow. NAD is the major carrier of E&P from fuels for synthesis of ATP (9). When glucose is the fuel, E&P must be transferred to free NAD c ϩ , reducing it to NADH c , before ATP synthesis. ATP is then synthesized in the cytosol by substrate phosphorylation followed by production of pyruvate that is oxidized in mitochondria for ATP synthesis by oxidative phosphorylation. E&P carried by NADH c also are transferred to mitochondrial NAD (NAD m ϩ ) via electron shuttles and fuel ATP synthesis by oxidative phosphorylation.The presence of lactate in resting tissues indicates that E&P are transferred to free NAD c ϩ and pyruvate is produced by glycolysis faster than they are used for ATP synthesis by means of oxidative phosphorylation; lactate dehydrogenase (LDH) reoxidizes ''exc...

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Section: Discussionmentioning

confidence: 45%

NADH augments blood flow in physiologically activated retina and visual cortex

Ido

Chang

Williamson

2004

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

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“…Collins et ai. (1987), Ackermann and Lear (1989), and Lear and Kasliwal (1991) have sug gested that loss of labeled lactate from brain to blood might account for the underestimation of CMRglc during activated conditions when assayed with [6_14C]glucose. The present results are consis tent with the possibility that lactate loss from acti vated tissue is an important factor in the underesti mation of CMRglc with [6_14C]glucose.…”

Section: Loss Of Labeled Metabolites Of [6-14 C)glucosementioning

confidence: 99%

Labeling of Metabolic Pools by [6-¹⁴C]Glucose during K⁺-Induced Stimulation of Glucose Utilization in Rat Brain

Adachi

Cruz

Sokoloff

et al. 1995

J Cereb Blood Flow Metab

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[6-14C]Glucose is the tracer sometimes recommended to assay cerebral glucose utilization (CMRglc) during transient or brief functional activations, but when used to study visual stimulation and seizures in other laboratories, it underestimated CMRglc. The metabolic fate of [6-14C]glucose during functional activation of cerebral metabolism is not known, and increased labeling of diffusible metabolites might explain underestimation of CMRglc and also reveal trafficking of metabolites. In the current studies cerebral cortex in conscious rats was unilaterally activated metabolically by KCl application, and CMRglc was determined in activated and contralateral control cortex with [6-14C]glucose or 2-[14C]deoxyglucose ([14C]DG) over a 5- to 7-min interval. Local 14C concentrations were determined by quantitative autoradiography. Labeled precursor and products were measured bilaterally in paired cortical samples from funnel-frozen brains. Left-right differences in 14C contents were small with [6-14C]glucose but strikingly obvious in [14C]DG autoradiographs. CMRglc determined with [6-14C]glucose was slightly increased in activated cortex but 40–80% below values obtained with [14C]DG. [14C]Lactate was a major metabolite of [6-14C]glucose in activated but not control cortex and increased proportionately with unlabeled lactate. These results demonstrate significant loss of labeled products of [6-14C]glucose from metabolically activated brain tissue and indicate that [14C]DG is the preferred tracer even during brief functional activations of brain.

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“…Because glucose metabolism exceeds oxygen consumption during increases in neuronal activity (3) another fate for lactate must also be sought. This might possibly occur through enhanced removal from the brain by flowing blood, a hypothesis for which we presently have only indirect evidence (68,69), or re-incorporation into astrocytic glycogen (70).…”

Section: Figmentioning

confidence: 99%

Behind the scenes of functional brain imaging: A historical and physiological perspective

Raichle

1998

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

560

330

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At the forefront of cognitive neuroscience research in normal humans are the new techniques of functional brain imaging: positron emission tomography and magnetic resonance imaging. The signal used by positron emission tomography is based on the fact that changes in the cellular activity of the brain of normal, awake humans and laboratory animals are accompanied almost invariably by changes in local blood flow. This robust, empirical relationship has fascinated scientists for well over a hundred years. Because the changes in blood flow are accompanied by lesser changes in oxygen consumption, local changes in brain oxygen content occur at the sites of activation and provide the basis for the signal used by magnetic resonance imaging. The biological basis for these signals is now an area of intense research stimulated by the interest in these tools for cognitive neuroscience research.Over the past 10 years the field of cognitive neuroscience has emerged as a very important growth area in neuroscience. Cognitive neuroscience combines the experimental strategies of cognitive psychology with various techniques to actually examine how brain function supports mental activities. Leading this research in normal humans are the new techniques of functional brain imaging: positron emission tomography (PET) and magnetic resonance imaging (MRI) along with event-related potentials obtained from electroencephalography or magnetoencephalography.The signal used by PET is based on the fact that changes in the cellular activity of the brain of normal, awake humans and unanesthetized laboratory animals are invariably accompanied by changes in local blood flow (for a review, see ref. 1). This robust, empirical relationship has fascinated scientists for well over a hundred years, but its cellular basis remains largely unexplained despite considerable research.More recently it has been appreciated that these changes in blood flow are accompanied by much smaller changes in oxygen consumption (2, 3). This leads to changes in the actual amount of oxygen remaining in blood vessels at the site of brain activation (i.e., the supply of oxygen is not matched precisely with the demand). Because MRI signal intensity is sensitive to the amount of oxygen carried by hemoglobin (4), this change in blood oxygen content at the site of brain activation can be detected with MRI (5-8).Studies with PET and MRI and magnetic resonance spectroscopy (MRS) have brought to light the fact that metabolic changes accompanying brain activation do not appear to follow exactly the time-honored notion of a close coupling between blood flow and the oxidative metabolism of glucose (9, 10). Changes in blood flow appear to be accompanied by changes in glucose utilization that exceed the increase in oxygen consumption (11, 12), suggesting that the oxidative metabolism of glucose may not supply all of the energy demands encountered transiently during brain activation. Rather, glycolysis alone may provide the energy needed for the transient changes in brain activity ...

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Autoradiographic Measurement of Cerebral Lactate Transport Rate Constants in Normal and Activated Conditions

Cited by 39 publications

References 32 publications

NADH augments blood flow in physiologically activated retina and visual cortex

NADH augments blood flow in physiologically activated retina and visual cortex

Labeling of Metabolic Pools by [6-¹⁴C]Glucose during K⁺-Induced Stimulation of Glucose Utilization in Rat Brain

Behind the scenes of functional brain imaging: A historical and physiological perspective

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Autoradiographic Measurement of Cerebral Lactate Transport Rate Constants in Normal and Activated Conditions

Cited by 39 publications

References 32 publications

NADH augments blood flow in physiologically activated retina and visual cortex

NADH augments blood flow in physiologically activated retina and visual cortex

Labeling of Metabolic Pools by [6-14C]Glucose during K+-Induced Stimulation of Glucose Utilization in Rat Brain

Behind the scenes of functional brain imaging: A historical and physiological perspective

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Product

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Labeling of Metabolic Pools by [6-¹⁴C]Glucose during K⁺-Induced Stimulation of Glucose Utilization in Rat Brain