Functional Activation of Cerebral Blood Flow and Metabolism before and after Global Ischemia of Rat Brain

Ueki, Minoru; Linn, F.; Hossmann, K.‐A.

doi:10.1038/jcbfm.1988.89

Cited by 214 publications

(166 citation statements)

References 26 publications

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“…Unfortunately the cerebrovascular effects of α-chloralose have not been extensively studied. The cerebral blood flow under α-chloralose anesthesia in the rat is between 0.69−0.85 ml/g/ min (Duong et al, 2000;Tsekos et al, 1998;Ueki et al, 1988), so the calculated ISO/AC ratio is 1.7−1.9. In the present study the mean initial drop in flow after MCAO was slightly larger in the α-chloralose group (p=0.053), and hyperemia during reperfusion was greater, due in part to the vasodilative features of isoflurane (Lorenz et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Alpha-chloralose is a suitable anesthetic for chronic focal cerebral ischemia studies in the rat: A comparative study

2008

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Abstractα-chloralose is widely used as an anesthetic in studies of the cerebrovasculature because it provides robust metabolic and hemodynamic responses to functional stimulation. However, there have been no controlled studies of focal ischemia in the rat under α-chloralose anesthesia. Artificially ventilated rats were prepared using 1.2−1.5 % isoflurane anesthesia for filament occlusion of the right middle cerebral artery (MCA), and anesthesia was either switched to α-chloralose (60 mg/kg bolus, 30 mg/ kg/hr; n=10) or was maintained on 1% isoflurane (n=10). Following temporary MCA occlusion EEG was monitored from a screw electrode and changes in cerebral blood flow (rCBF) measured with a laser Doppler probe placed over the ischemic cortex. This study shows that α-chloralose is a safe anesthetic for ischemia studies and provides excellent survival. Compared with isoflurane, the cortical and total infarct volumes are larger in the α-chloralose anesthetized animals, while the functional outcome at 72 hours is similar. The total duration of peri-infarct flow transients (PIFTs) is also significantly longer in α-chloralose anesthetized animals. The average amplitude of the flow transients showed a good correlation with the extent of edema in all animals as did the total duration of non-convulsive seizures (NCS) in the α-chloralose anesthetized animals.

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Section: Discussionmentioning

confidence: 99%

Alpha-chloralose is a suitable anesthetic for chronic focal cerebral ischemia studies in the rat: A comparative study

2008

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“…Reduction of pyruvate to lactate results in a rise in tissue lactate levels, which has been demonstrated in animals (22,23) and in humans with magnetic resonance spectroscopy (24-27) during brain activation. It has been proposed that a third pathway for regeneration of NAD ϩ occurs during activation, which increases NADH oxidation through signaling pathways that promote production of nitric oxide with subsequent increase in blood flow (8,11).…”

Section: Discussionmentioning

confidence: 99%

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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“…4). Accumulation of lactate in rat cerebral cortex during forepaw stimulation (10) and in visual cortex during photostimulation (11,12) attests to (i) increased transfer of E&P from glucose to free NAD c ϩ and formation of pyruvate faster than they are used for oxidative phosphorylation by astrocytes and neurons combined, and (ii) increased transfer of E&P from free NADH c to pyruvate by LDH to form lactate. E&P carried by free NADH c in stimulated retina and visual cortex (potentially equimolar to pyruvate oxidized in mitochondria) also can be transferred to oxidized substrates of enzymes in metabolic pathways that activate constitutive NOS (cNOS) to increase blood flow (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Elevated lactate levels in working tissues (10)(11)(12) attest to increased glycolysis and corresponding increased rates of transfer of E&P to NAD c ϩ .…”

mentioning

confidence: 99%

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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Functional Activation of Cerebral Blood Flow and Metabolism before and after Global Ischemia of Rat Brain

Cited by 214 publications

References 26 publications

Alpha-chloralose is a suitable anesthetic for chronic focal cerebral ischemia studies in the rat: A comparative study

Alpha-chloralose is a suitable anesthetic for chronic focal cerebral ischemia studies in the rat: A comparative study

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

NADH augments blood flow in physiologically activated retina and visual cortex

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